Abstract
Background:
HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque.
Methods:
This cross-sectional study included participants from the MACS/WIHS Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from six areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for associations of HIV- and HCV-related factors with echomorphologic features.
Results:
Of 2,655 participants (65% women, median age 44 [interquartile range 37–50]), 1,845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4+ count <200 cells/μL had significantly higher prevalence of echolucent plaque (aPR 1.86, CI 1.08–3.21) than those without HIV. HCV infection alone (aPR 1.86, CI 1.08–3.19) and HIV-HCV coinfection (aPR 1.75, CI 1.10–2.78) were each associated with higher prevalence of echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR 2.75, CI 1.03–7.32) compared to people without HIV and HCV.
Conclusions:
HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque.
Keywords: HIV, HCV, atherosclerosis, carotid ultrasound
Introduction
Advances in antiretroviral therapy (ART) have extended the life expectancy of people living with HIV (PLWH).1 Despite the availability of better treatment options and improved outcomes, PLWH remain at significantly higher risk of adverse cardiovascular events compared to their uninfected counterparts.2,3 This higher cardiovascular risk likely results from the interplay between classic risk factors and other unique features related to HIV infection, including chronic inflammation, side effects of some antiretroviral medications, and behavioral elements, among other factors, that can activate pro-atherogenic immune responses.4–7
Previous studies have shown that HIV is associated with an accelerated progression of carotid atherosclerotic disease and stroke.3,4,8–12 Furthermore, hepatitis C virus (HCV) infection is relatively common among PLWH.13 The impact of HCV alone or with HIV coinfection on cardiovascular events has been assessed; however, the results are inconsistent, and the effects of coinfection on stroke remain poorly characterized.14–17
Despite a growing understanding of the association of HIV with atherosclerosis and stroke, it is still unknown whether carotid atherosclerotic plaques in PLWH have unique echomorphologic features that may lead to a higher cerebrovascular risk profile. The impact of HCV coinfection on plaque characteristics is also unclear. In this study, we assessed ultrasonographic features of plaque in participants from the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS) with and without HIV.
Methods
This study was conducted in adherence to STROBE guidelines. Access to individual-level data from the MACS/WIHS Combined Cohort Study (MWCCS) may be obtained upon review and approval of an MWCCS concept sheet (https://statepi.jhsph.edu/mwccs/work-with-us/).
Participants.
The MACS and WIHS were two extensive, well-characterized longitudinal cohort studies of PLWH and otherwise similar persons without HIV.18,19 In 2019, the cohorts merged to form the MWCCS.20 In the current investigation, we examined in a cross-sectional study a subset of MACS and WIHS participants who were enrolled in vascular substudies beginning in 2004.4,8 The vascular substudies included were performed during visits 41–44 for MACS and visits 20–22 for WIHS. For more details, refer to Supplemental Methods. All individuals provided informed consent, and studies were approved by each site’s Institutional Review Board.
Carotid Artery Ultrasound and Assessment of Plaque Echomorphologic Features.
High-resolution B-mode carotid artery ultrasound evaluated six locations in each participant’s right carotid artery using a standardized method across all study sites, as previously described.4,8,21 Maximal plaque thickness was obtained at the thickest region of the plaque, and measurement was performed perpendicularly to the arterial wall. Carotid artery plaques, defined as a localized intima-media thickening ≥1.5 mm, were categorized based on relative echogenicity, surface, and texture (Figure 1).22–26 If >1 plaque was present at a location, the largest plaque in one view was characterized. Up to three plaques were characterized per participant. To eliminate inter-reader variability, a single reader performed plaque feature interpretations. For more details, refer to Supplemental Methods.
Figure 1.
Examples of carotid artery atherosclerotic plaques visualized with B-mode ultrasound. Arrows indicating (A) multiple carotid artery plaques located at the carotid artery bifurcation and internal carotid artery, and (B) single carotid artery plaque located on the posterior wall of the carotid artery bifurcation extending into the internal carotid artery.
Exposures of Interest.
Primary exposures of interest included HIV serostatus, ascertained by ELISA and confirmed by Western blot; HIV viral suppression (≤80 copies/mL [WIHS], ≤50 copies/mL [MACS]); current CD4+ T-cell count (cells/μL); and HCV coinfection status. HCV coinfection status was determined by either HCV antibody testing or detectable viremia; because scans occurred before the era of direct-acting antivirals, HCV treatment status was not considered. Exposures were assessed based on data available at the core study visit closest in time to the carotid scan.
Analysis.
Baseline characteristics of participants are shown as medians with interquartile range (IQR) or numbers with percentages. Differences in proportions by HIV serostatus were assessed with the chi-square test. To account for the potential for up to 3 plaques per participant, each with its own unique set of echomorphologic features, data were structured such that each participant had two repeated outcomes, with each outcome defined as the number of plaques within a particular echomorphologic category and an indicator variable defining the category. Using echolucency as an example, each participant contributed one outcome with the number of echogenic plaques identified and an echolucency indicator variable (e.g., 0 as the reference group) and a second outcome with the number of echogenic plaques identified and the same echolucency indicator variable (e.g., 1 as the comparison group). To assess associations between variables of interest and plaque echomorphologic characteristics, Poisson regression with generalized estimating equations was used to estimate adjusted prevalence ratios (aPR) between variables of interest and plaque characteristics, considering the dependency of the two outcomes per participant by an exchangeable correlation structure. The models also directly tested for a difference between the magnitude of the associations of each variable of interest and the two outcomes. All multivariable models adjusted for demographic characteristics (age, race/ethnicity, education, income, study site), behavioral characteristics (history of injection drug use, crack/cocaine use, current smoking, current alcohol use, history of HCV), and cardiometabolic risk factors (body mass index, systolic blood pressure, total and HDL cholesterol, use of antihypertensive medications, use of cholesterol-lowering drugs, history of diabetes). For models with HIV-related factors, analyses additionally controlled for current CD4 T-cell count, ART use in the past six months, and history of clinical AIDS. For main effects, we considered p<0.05 statistically significant and evaluated effect modification by sex at birth using two-way interaction terms. For interaction, we considered a less narrow threshold for statistical significance (p<0.10). Missing data were handled using a complete case analysis approach for multivariable analyses (Supplemental Methods).
Statistical analyses were performed using R v3.6.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Study population characteristics.
For this analysis all participants with carotid ultrasound were included. A total of 1,723 women (1,231 with HIV) and 932 men (614 with HIV) had carotid ultrasound data (Table 1). Women with plaques were a median 47 years old (IQR 43–52), with self-reported 60% Black, 20% Hispanic, 20% White, and 0.6% other race/ethnicity (Table 1). We identified 191 plaques in 129 women with HIV and 51 in 32 women without HIV, with a median number of plaques of 1 (IQR 1–2) among those with plaque in both groups, respectively (Table 2). Men with plaques were a median 53 years old (IQR 48–58), with 24% Black, 4% Hispanic, 72% White, and 0.8% other race/ethnicity (Table 1). We identified 248 plaques in 171 men with HIV and 139 plaques in 93 men without HIV, with a median number of plaques of 1 (IQR 1–2) among those with plaque in both groups (Table 2).
Table 1.
Characteristics of study participants =at baseline carotid artery scan, by sex at birth, presence of plaque, and HIV serostatus.
| Women | Men | |||||||
|---|---|---|---|---|---|---|---|---|
| All HIV+ | With Plaques | All | With Plaques | All | With Plaques | All | With Plaques | |
| HIV+ (N=1,231) | HIV+ (N=129) | HIV− (N=492) | HIV− (N=32) | HIV+ (N=614) | HIV+ (N=171) | HIV− (N=318) | HIV− (N=93) | |
| Demographics | ||||||||
| Age, years (median, IQR) | 41 (35–47) | 48 (44–52) | 37 (29–44) | 45 (40.8–51) | 48 (44–53) | 52 (47–56) | 52 (46–58) | 57 (52–61) |
| Race/ethnicity (number, %) | ||||||||
| Black, non-Hispanic | 713 (57.9) | 74 (57.4) | 303 (61.6) | 22 (68.8) | 179 (29.2) | 46 (26.9) | 75 (23.6) | 16 (17.2) |
| Hispanic | 357 (29) | 24 (18.6) | 136 (27.6) | 8 (25) | 52 (8.5) | 8 (4.7) | 23 (7.2) | 2 (2.2) |
| White, non-Hispanic | 135 (11) | 30 (23.3) | 43 (8.7) | 2 (6.2) | 377 (61.4) | 115 (67.3) | 220 (69.2) | 75 (80.6) |
| Other | 26 (2.1) | 1 (0.8) | 10 (2) | 0 (0) | 6 (1) | 2 (1.2) | 0 (0) | 0 (0) |
| Comorbidities | ||||||||
| Current smoker (number, %) | 535 (43.5) | 73 (56.6) | 247 (50.3) | 27 (84.4) | 193 (31.9) | 66 (39.5) | 83 (26.1) | 28 (30.1) |
| Self-reported menopause (number, %) | 280 (22.8) | 62 (48.1) | 60 (12.2) | 9 (28.1) | ||||
| Body mass index, kg/m2 (median, IQR) | 27 (23.6–31.6) | 24.9 (21.7–30.6) | 29.2 (24.5–35.3) | 25.8 (23.2–32.8) | 25 (22.6–27.6) | 24.9 (22.6–27.4) | 26 (24–28.9) | 26.1 (24.1–29) |
| Current use of anti-hypertensive medications (number, %) | 235 (19.1) | 33 (25.6) | 68 (13.8) | 13 (40.6) | 134 (22) | 52 (30.8) | 79 (24.8) | 28 (30.1) |
| Current use of lipid lowering medications (number, %) | 77 (6.3) | 7 (5.4) | 8 (1.6) | 2 (6.2) | 166 (27.3) | 56 (33.3) | 58 (18.2) | 30 (32.3) |
| History of diabetes (number, %) | 158 (12.8) | 24 (18.6) | 63 (12.8) | 10 (31.2) | 59 (10.2) | 17 (10.8) | 34 (11.4) | 12 (13.8) |
| History of hepatitis C infection (number, %) | 382 (31) | 76 (58.9) | 90 (18.3) | 13 (40.6) | 101 (16.6) | 34 (20.2) | 27 (8.5) | 8 (8.6) |
| HIV-specific characteristics | ||||||||
| Baseline CD4+ T-cell count, cells/mm3 (median, IQR) | 431 (262–631) | 334 (192–536) | 1002 (797–1253.5) | 953 (736–1189) | 506.5 (349.8–687) | 535.5 (356.8–688) | 919 (723.2–1127.2) | 946 (693–1140) |
| Baseline HIV-1 viral load, copies/mL (median, IQR) | 250 (80–8550) | 750 (80–19000) | 40 (40–2214.5) | 40 (40–1055.2) | ||||
| Undetectable baseline HIV-1 viral load (number, %) | 538 (43.7) | 46 (35.7) | 356 (58.6) | 104 (61.9) | ||||
| History of clinical AIDS (number, %) | 449 (36.5) | 62 (48.1) | 85 (13.8) | 31 (18.1) | ||||
| Potent ART use in past 6 months (number, %) | 768 (62.4) | 78 (60.5) | 437 (71.6) | 122 (72.2) | ||||
| Cumulative exposure of potent ART*, years (median, IQR) | 3 (1–6) | 5 (2–7) | 4.5 (2–7) | 4.9 (2.1–7.2) | ||||
| of PIs, years (median, IQR) | 1.5 (0–4) | 2.5 (0–5) | 3.2 (0–6.2) | 4.2 (0.4–7.3) | ||||
| of NNRTIs, years (median, IQR) | 0.5 (0–2.5) | 1.5 (0–3.5) | 1.4 (0–4.1) | 2 (0–4.4) | ||||
| of NRTIs, years (median, IQR) | 3.5 (2–8) | 7 (3–9) | 6.8 (3.3–9.6) | 7.2 (4–9.7) | ||||
| Nadir CD4+ T-cell count before ART use, cells/mm3 (median, IQR) | 274 (163–398) | 224 (142–348) | 278.5 (155.2–400) | 268 (141.8–359) | ||||
AIDS = acquired immunodeficiency syndrome, ART = antiretroviral therapy, HIV = human immunodeficiency virus, IQR = interquartile range, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor.
All characteristics assessed at baseline unless otherwise noted.
Among those using ART at baseline.
Table 2.
Echomorphologic characteristics of plaques, by sex at birth and HIV serostatus.
| Women | Men | |||||
|---|---|---|---|---|---|---|
| HIV+ (N=129) | HIV− (N=32) | P-value | HIV+ (N=171) | HIV− (N=93) | P-value | |
| Echolucency | 0.152 | 0.673 | ||||
| Echolucent (100% of plaque is echolucent) (number, %) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
| Predominantly echolucent (>50% of plaque is echolucent) (number, %) | 80 (41.88) | 16 (31.37) | 119 (48) | 70 (50) | ||
| Predominantly echogenic (>50% of plaque is echogenic) (number, %) | 110 (57.59) | 34 (66.67) | 129 (52) | 69 (50) | ||
| Echogenic (100% of plaque is echogenic) (number, %) | 0 (0) | 1 (1.96) | 0 (0) | 0 (0) | ||
| Calcification (requires acoustic shadowing) (number, %) | 1 (0.52) | 0 (0) | 0 (0) | 0 (0) | ||
| Texture | ||||||
| Homogenous texture (number, %) | 0 (0) | 0 (0) | - | 0 (0) | 0 (0) | - |
| Heterogenous texture (i.e., patchy plaques) (number, %) | 191 (100) | 51 (100) | 248 (100) | 139 (100) | ||
| Surface | 0.178 | 0.438 | ||||
| Smooth surface (number, %) | 44 (23.04) | 7 (13.73) | 9 (4) | 8 (6) | ||
| Irregular surface (height variations seen along the contour of the lesion) (number, %) | 147 (76.96) | 44 (86.27) | 239 (96) | 131 (94) | ||
| Ulceration (i.e., a discrete depression >2 mm in width extending into the media) (number, %) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
| Maximum carotid plaque thickness (mm) (median, IQR) | 2.29 (1.97–2.81) | 2.63 (2.15–3.06) | 0.023 | 2.38 (1.98–2.94) | 2.14 (1.84–2.66) | 0.005 |
| Number of plaques (number) | 191 | 51 | 248 | 139 | ||
IQR= interquartile range.
Plaque characteristics.
All identified plaques were of heterogeneous texture, and none had ulcerations. Within each cohort, echolucency and surface characteristic distributions were similar between participants with and without HIV (Table 2). The maximal plaque thickness was significantly smaller among women with HIV versus without HIV (median 2.29 mm, IQR 1.97–2.81 vs. 2.63 mm, IQR 2.15–3.06; p=0.02). In men with HIV, the maximal plaque thickness was significantly larger among those with versus without HIV (median 2.38 mm, IQR 1.98–2.94, vs. 2.14 mm, IQR 1.84–2.66; p=0.005).
Associations of HIV-related factors with plaque echomorphologic characteristics.
After adjustment for demographic characteristics, behavioral characteristics, cardiometabolic risk factors, and HIV-related factors, compared to participants without HIV, participants with HIV and current CD4+ count <200 cells/μL had a higher prevalence of echolucent plaques (aPR 1.86, 95% CI 1.08–3.21, p=0.02). In a dose-response manner, lower CD4+ count was also associated with echogenic plaque (p-trend 0.003), with CD4+ count <200 cells/μL associated with a significantly higher prevalence of echogenic plaque (aPR 2.61, 95% CI 1.67–4.08, p<0.005) compared with participants without HIV. Analyses controlling for potential confounders showed that HCV infection alone (aPR 1.86, 95% CI 1.08–3.19, p=0.02) or coinfection with HIV and HCV (aPR 1.75, 95% CI 1.1–2.78, p=0.02) remained associated with higher prevalence of echogenic plaque.
In a dose-response manner, after confounder adjustment, lower CD4+ count was associated with irregular surface plaque (p-trend 0.013), with CD4+ count <200 cells/μL associated with a significantly higher prevalence of irregular surface plaque (aPR 2.26, 95% CI 1.51–3.4, p<0.005) compared with those without HIV. HIV and HCV coinfection was also associated with smooth surface plaques (aPR 2.75, 95% CI 1.03–7.32, p=0.043). There was no evidence of effect modification by sex at birth for any echomorphologic features of plaque (all p-interaction >0.10) (Tables 3–4).
Table 3.
Association between HIV serostatus and plaque echogenicity
| Echolucent Plaque† | Echogenic Plaque‡ | |||||||
|---|---|---|---|---|---|---|---|---|
| aPR | 95% CI | P-value | P trend | aPR | 95% CI | P-value | P trend | |
| HIV serostatus (ref: HIV-negative) | 1.10 | 0.75–1.60 | 0.629 | 1.15 | 0.81–1.63 | 0.432 | ||
| Viral suppression (ref: HIV negative) | ||||||||
| HIV-positive, suppressed | 1.15 | 0.76–1.74 | 0.496 | 1.13 | 0.75–1.69 | 0.564 | ||
| HIV-positive, unsuppressed | 1.04 | 0.68–1.60 | 0.849 | 0.934 | 1.18 | 0.82–1.70 | 0.383 | 0.442 |
| Current CD4+ count (cells/uL) (ref: HIV negative) | ||||||||
| 500+ cells/uL | 1.17 | 0.79–1.74 | 0.431 | 1.09 | 0.75–1.58 | 0.650 | ||
| 200–499 cells/uL | 1.06 | 0.71–1.59 | 0.764 | 1.11 | 0.75–1.63 | 0.609 | ||
| <200 cells/uL | 1.86 | 1.08–3.21 | 0.025 | 0.110 | 2.61 | 1.67–4.08 | <0.005 | 0.003 |
| HCV coinfection (ref: HIV− and HCV −) | ||||||||
| HIV-positive, HCV-negative | 1.06 | 0.71–1.58 | 0.780 | 1.18 | 0.80–1.74 | 0.408 | ||
| HIV-negative, HCV-positive | 0.74 | 0.30–1.82 | 0.511 | 1.86 | 1.08–3.19 | 0.025 | ||
| HIV-positive, HCV-positive | 1.25 | 0.77–2.03 | 0.372 | 1.75 | 1.10–2.78 | 0.019 | ||
aPR: adjusted prevalence ratio.
Table 4.
Association between HIV serostatus and plaque surface characteristics
| Smooth Surface | Irregular Surface † | |||||||
|---|---|---|---|---|---|---|---|---|
| aPR | 95% CI | P-value | P trend | aPR | 95% CI | P-value | P trend | |
| HIV serostatus (ref: HIV-negative) | 1.59 | 0.70–3.60 | 0.264 | 1.08 | 0.79–1.47 | 0.623 | ||
| Viral suppression (ref: HIV negative) | ||||||||
| HIV-positive, suppressed | 1.12 | 0.45–2.79 | 0.802 | 1.14 | 0.80–1.62 | 0.467 | ||
| HIV-positive, unsuppressed | 2.09 | 0.89–4.90 | 0.090 | 0.080 | 1.02 | 0.73–1.43 | 0.894 | 0.989 |
| Current CD4+ count (cells/uL) (ref: HIV negative) | ||||||||
| 500+ cells/uL | 1.47 | 0.59–3.66 | 0.409 | 1.09 | 0.80–1.49 | 0.569 | ||
| 200–499 cells/uL | 1.90 | 0.79–4.53 | 0.150 | 1.01 | 0.73–1.40 | 0.959 | ||
| <200 cells/uL | 2.34 | 0.83–6.61 | 0.110 | 0.052 | 2.26 | 1.51–3.40 | <0.005 | 0.013 |
| HCV coinfection (ref: HIV− and HCV −) | ||||||||
| HIV-positive, HCV-negative | 1.21 | 0.49–3.00 | 0.685 | 1.11 | 0.80–1.54 | 0.526 | ||
| HIV-negative, HCV-positive | 0.99 | 0.12–8.42 | 0.995 | 1.34 | 0.79–2.28 | 0.279 | ||
| HIV-positive, HCV-positive | 2.75 | 1.03–7.32 | 0.043 | 1.38 | 0.92–2.06 | 0.123 | ||
Irregular Surface: includes plaques with irregular surface (i.e., height variations seen along the contour of the lesion) and plaques with ulceration (i.e., a discrete depression >2 mm in width extending into the media).
Associations of baseline characteristics with plaque echomorphologic characteristics.
After confounder adjustment, older age, male sex, White race (versus Black race), current smoking, higher systolic blood pressure, higher total cholesterol, low HDL cholesterol and use of lipid-lowering agents were associated with higher prevalence of echolucent plaques across both cohorts (Table S1). Additionally, older age, intravenous drug use, current smoking, lower BMI, higher systolic blood pressure, use of antihypertensive medication, and higher total cholesterol were associated with an increased prevalence of echogenic plaques (Table S1). Moreover, education more than college level and higher income were associated with a lower prevalence of echogenic plaques (Table S1). Finally, we observed statistically significant differences in associations of income and lipid-lowering medication use with echogenic plaque, as compared with associations of these factors with echolucent plaque. This suggests a differential impact of income and lipid-lowering medication use on echomorphology of carotid plaque (Table S1).
After similar confounder adjustment, older age, female sex, intravenous drug use, and current smoking were associated with a higher prevalence of smooth surface plaques across both cohorts (Table S2). Moreover, education more than college and higher income were associated with a lower prevalence of smooth surface plaques (Table S2). Additionally, older age, male sex, White race, current smoking, lower BMI, higher systolic blood pressure, use of antihypertensives medication, higher total cholesterol, and use of lipid-lowering agents were associated with an increased prevalence of irregular surface plaques (Table S2). Finally, we observed statistically significant differences in associations of age, sex, race/ethnicity, education level, and income with irregular surface plaques, as compared with associations of these factors with smooth surface plaques. This indicates a differential impact of these factors on surface characteristics of carotid plaque (Table S2).
Discussion
This cross-sectional study included longitudinally-followed, well-characterized, middle-aged men and women from the MACS and WIHS to assess associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque. After controlling for multiple potential confounders, we found that participants with HIV with CD4+ cell count <200 cells/μL had a higher prevalence of echolucent and echogenic plaques, as well as plaques with irregular surface, compared with people without HIV. Furthermore, HCV alone or combined with HIV was associated with a higher prevalence of echogenic plaques. Finally, HIV-HCV coinfection was linked with a higher prevalence of smooth surface plaques.
Despite significant efforts in the field, the precise underlying mechanisms for accelerated atherosclerosis observed in PLWH remain elusive. Our group described that in the MACS and WIHS, there was an association between HIV and subclinical carotid atherosclerotic plaque formation, even among those virologically suppressed.4 In the same cohorts, carotid atherosclerotic plaques and arterial stiffness were associated with mortality.27 Jung et al.10 utilized a plaque gray scale median approach to characterize the echomorphology of the intima-media complex of the carotid artery in the absence of plaque in a cross-sectional study of participants from the WIHS. These authors described no grayscale median differences between women with versus without HIV. Furthermore, in the same analyses, other lipid and non-lipid-related risk factors were associated with variations of carotid atherosclerosis of this parameter.10 The current analysis extends this work by focusing on echomorphologic plaque features, which may relate to more vulnerable, and therefore pathogenic, atherosclerotic plaques.
Similar to HIV infection, HCV is also tied to systemic inflammation, leading to a myriad of extrahepatic manifestations, including cardiovascular events.28,29 HCV has also been related to a higher risk of carotid artery intima-media thickening, carotid artery atherosclerosis plaque formation, and strokes.14,30 Given the high prevalence of HCV coinfection in PLWH31, there has been significant interest in understanding the impact of HIV-HCV coinfection on cardiovascular outcomes. A prior WIHS study showed a non-significant association of either HIV or HCV mono-infection with left ventricular (LV) dysfunction. However, the combined effect was significantly associated with LV dysfunction.16 Other studies have also shown that HIV-HCV coinfection is associated with a higher risk of cardiovascular events in general, and in particular strokes, than in those with HIV monoinfection.32
Our study showed that people with HIV and a CD4+ cell count <200 cells/μL had a higher prevalence of echolucent, echogenic, and irregular surface plaque compared to both people without HIV and people with HIV with higher CD4 counts. This suggests that more severe HIV disease relates to plaque in general, including those with high-risk features, i.e., echolucent and irregular surface plaques. These vulnerable plaques might be a crucial pathophysiological step in the increased risk of stroke previously observed in PLWH. Another relevant finding is that HCV alone or combined with HIV correlated with a higher risk of echogenic plaques. Furthermore, HIV-HCV coinfection was linked with smooth surface plaques. These findings suggest that the plaques observed in the context of HCV infection may be more stable and lower-risk plaques. With few exceptions,15 most prior studies have shown an increased risk of carotid artery atherosclerosis disease and strokes among people with HCV infection alone or in coexistence with HIV.14,30,33 Additionally, a MACS study by McKibben et al.34 described that after adjustment for several confounders, including HIV serostatus, HCV infection was associated with a higher prevalence of coronary artery plaques and noncalcified plaques. Our findings of higher prevalence of certain atherosclerosis plaques in people with HIV-HCV coinfection or HCV mono-infection is consistent with prior studies, including those exploring other arteries. However, the presence of plaques with more “stable” features do not align with the clinical neurologic outcomes described previously with these infections. It is essential to consider that stroke etiology can differ from carotid artery atherosclerosis plaque rupture. Other mechanisms can lead to or contribute to cerebrovascular complications, which might be the case for HCV infection or HIV-HCV coinfection. Lastly, we observed a distinct distribution of plaque maximal thickness between women and men with versus without HIV. While this finding is intriguing, plaque thickness was not an a priori outcome of interest and therefore beyond the scope of our study, but warrants further investigation.
To the best of our knowledge, this is the first study comprehensively evaluating echomorphologic features of carotid artery plaque in a large group of women and men with or at risk of HIV. The data source for this study are two of the largest and longest, well-characterized cohorts that aim to understand the natural history of HIV. Although these results are highly relevant to understand the pathophysiology of atherosclerosis in PLWH, this study has limitations. One is that our study is cross-sectional, which inherently limits causal inference. This might explain the counterintuitive association between use of lipid-lowering agents and higher prevalence of echolucent and irregular surface plaques. These associations likely represent lipid-lowering agent use as a marker of cardiovascular risk, rather than as a direct cause of abnormal plaque morphology. The latter question potentially be assessed in a longitudinal study or randomized controlled trial. Furthermore, no clinical outcome data were available for this analysis; therefore, we could not evaluate the relationship between plaque morphology and events such as stroke or myocardial infarction. Another limitation is that the method utilized to assess plaque morphology is relatively subjective and dependent on reader interpretation. To eliminate bias from inter-reader differences in interpreting the images, all images were evaluated by a single expert reader. Additionally, our group has consistently reported results from the right carotid ultrasound only.11,35–37 The main reason for this was to minimize staff time required and testing burden for participants. The notion that comparable information on atherosclerotic disease burden can be obtained from either the left or right side alone is supported by previous findings showing similar degree of atherosclerosis in both carotid arteries.38,39 Our own experience as well as those of other groups supports the approach of using measurements of either the right or left carotid artery to classify participants in terms of their overall vascular disease burden. Lastly, while the MACS/WIHS is representative of older U.S. PLWH, generalizability outside the U.S. should be considered carefully.
In conclusion, in this large cross-sectional study from the MACS and WIHS, we found that poorly controlled HIV infection, i.e., CD4+ cell count <200 cells/μL, was associated with echolucent, echogenic, and irregular surface plaques. In addition, HCV alone or in combination with HIV was associated with an increased risk of echogenic plaques. Finally, HIV-HCV coinfection showed an association with smooth surface plaques. Understanding atherosclerosis morphology in PLWH and those with HCV coinfection may provide critical prognostic information unique to this population. Further studies are necessary to fully understand the association of carotid atherosclerosis plaque morphology and outcomes in PLWH with or without coexisting HCV infection.
Supplementary Material
Acknowledgments
Data were collected by MACS and WIHS, now MWCCS. Contents of this publication are solely the responsibility of the authors and do not represent official views of the National Institutes of Health (NIH). Authors gratefully acknowledge contributions of study participants and dedication of staff at MWCCS sites.
Funding Sources
MWCCS sites contributing data: Baltimore, U01-HL146201; Bronx, U01-HL146204; Brooklyn, U01-HL146202; Data Analysis and Coordination Center, U01-HL146193; Chicago-Cook County, U01-HL146245; Chicago-Northwestern, U01-HL146240; Northern California, U01-HL146242; Los Angeles, U01-HL146333; Metropolitan Washington, U01-HL146205; Pittsburgh, U01-HL146208. MWCCS is funded primarily by the National Heart, Lung, and Blood Institute, with additional co-funding from these NIH institutes: NICHD, NIA, NIDCR, NIAID, NINDS, NIMH, NIDA, NINR, NCI, NIAAA, NIDCD, NIDDK, NIMHD, and in coordination and alignment with research priorities of the Office of AIDS Research. MWCCS data collection is supported by UL1-TR000004, UL1-TR003098, UL1-TR001881, P30-AI-050409, P30-AI-073961, P30-AI-050410, P30-AI-027767, P30-MH-116867, UL1-TR001409, KL2-TR001432, TL1-TR001431. Additional funding: 5R01HL144937-03 (Research Supplement to C.A.B.), R21-AG-060860, R01-HL-083760, R01-HL-095140, R01-HL-126543, R01-HL-140976, R01-HL-148094, R01-HL-095129, R01-HL-125053, K01-HL-137557. Full acknowledgment of funding: https://statepi.jhsph.edu/mwccs/acknowledgements/.
Disclosures
C.J.R.: compensation from Merck, Pfizer for other services; grants from Amgen, NHLBI, American Heart Association.
P.C.T.: intellectual property; grants from Merck, Gilead Sciences.
F.J.P.: compensation from Janssen Pharmaceuticals, Gilead Sciences, ViiV Healthcare Company for other services.
Non-standard Abbreviations/Acronyms
- aPR
adjusted prevalence ratio
- ART
antiretroviral therapy
- HCV
hepatitis C virus
- LV
left ventricular
- MACS
Multicenter AIDS Cohort Study
- MWCCS
MACS/WIHS Combined Cohort Study
- PLWH
people living with HIV
- WIHS
Women’s Interagency HIV Study
Footnotes
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