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Associations Between Central Obesity and Lifelong Antiviral Therapy in Adults Living With HIV Acquired From Early Childhood
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In conclusion, individuals who acquired HIV in early childhood were more likely to demonstrate central obesity compared with those without HIV. Using DEXA scans and anthropometrics, we measured body fat distribution over an average of 7 years. We also identified associations between body composition and metabolic parameters as well as the duration of exposure to certain ARVs. These findings underscore the long-term persistence and associated risk factors of central adiposity among PLWH who have lifelong ARV exposure which may translate to increased metabolic disturbances and enhanced risk of cardiovascular disorders in future decades.
Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P < 0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = -0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).
This study presents strong evidence for persistent and worsening central adiposity in young adults [perinatal HIV] with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.
In this natural history study, young adults who acquired HIV in early childhood demonstrated a heightened risk for metabolic disorders compared with those without HIV. Hyperlipidemia and insulin resistance were both strikingly common among PLWH. Body fat distribution also tended to be central with adipose tissue accumulation preferentially in the truncal region, relative to those without HIV. Although BMI and biomarkers for lipid and glucose metabolism did not change significantly between baseline and last follow-up, noticeable increases inwaist to hip circumference ratio and trunk to limb fat ratio were observed and may reflect the residual lipodystrophic effects of extensive ARV use since early childhood and adolescence.
Lipid biomarkers for cardiovascular health normally worsen with age as a result of certain changes in diet and lifestyle.19,20 We observed the opposite trend during follow-up among PLWH, with a significant increase in HDL-cholesterol with small, but nonsignificant, decreases in log-transformed triglycerides and cholesterol. These changes could be a result of unique factors, including wider availability of dietary and lifestyle guidance as well as closer health monitoring associated with living with a chronic health condition.21 The use of lipid-lowering medications may have also contributed to the observed changes in lipids in the present cohort. Alternatively, it may represent a correction of PI-induced dyslipidemia from baseline with less exposure to certain PIs in particular.8,22 We previously reported a 52% prevalence of hypertriglyceridemia in a subset of this cohort during their adolescence.2 In this study, the rate of hypertriglyceridemia was 17% at the last follow-up visit, although it was still higher relative to controls. The number of PLWH on a PI-based agent decreased from 22 of 40 to 16 of 40 over follow-up, and those who remained tended to receive ritonavir-boosted agents with more favorable lipid profile effects.23 In addition, compared with healthy volunteers, we found higher triglycerides and lower HDL-cholesterol in the PLWH, 84% of whom had lifetime exposure to either nelfinavir or ritonavir. Although none of the lipid biomarkers correlated with ARV exposure, we found that nelfinavir and ritonavir were correlated with trunk to limb fat ratio and waist to hip ratio, respectively. The observed lipid alterations may be indirectly driven by exposure to these agents through residual central adiposity acquired in childhood and adolescence. Overall, although dyslipidemia tended to improve, 20% of PLWH were receiving lipid-lowering medications during follow-up. PLWH had comparatively worse lipid profiles relative to those without HIV which may be associated with persistent alterations in body composition. As this cohort ages, monitoring for lipid biomarkers with abdominal obesity warrants continued attention to reduce the risk for cardiovascular disorders.
The use of a tenofovir-based regimen among most of our cohort could account for some of the observed improvements in insulin resistance and dyslipidemia during follow-up. The TULIP study group demonstrated that tenofovir/FTC, when added to PI monotherapy, may have lipid-lowering effects.26 Furthermore, the increased use of tenofovir/FTC over the NRTIs stavudine and didanosine may account for the observed protective effect of greater exposure to emtricitabine on trunk to limb fat ratio during follow-up, considering that the 2 agents are typically coformulated. Although it was nonsignificant, longer exposure to tenofovir over follow-up tended to be associated with a lower increase in trunk to limb fat ratio. In a 12-year longitudinal study of HIV-infected adult men, Price et al21 also demonstrated that switching from stavudine to abacavir or tenofovir was associated with a reduced likelihood of lipodystrophy. We also identified that the trunk to limb fat ratio was more strongly correlated with cumulative exposure to stavudine compared with tenofovir. When we analyzed the relationship between change in trunk to limb fat ratio with change in duration of exposure to individual agents over follow-up, continued exposure to didanosine was linked with worsening trunk to limb fat ratio. These relationships remained significant even after adjusting for the duration of follow-up.
Previous literature indicates switching from PI-based therapy to nevirapine-containing regimens may result in a more favorable lipid profile.27-29 Although nevirapine use was not significantly associated with lipid levels, we identified a deleterious association between greater exposure to nevirapine and waist to hip ratio. Central obesity has been previously associated with nevirapine-containing regimens in PI-naive individuals.30 In children, nevirapine-based treatment was also associated with a greater prevalence of central hypertrophy.31 Thus, our finding, although limited by the small sample size and shorter duration of exposures, is in agreement with previous observations of the effects of nevirapine use on central obesity.
People living with HIV (PLWH) from the earliest generation of children with transfusion-acquired and perinatal transmissions are now adults approaching their fourth decade of life with extensive ARV exposure. Metabolic complications and lipodystrophy contribute to insulin resistance, hyperlipidemia, and endothelial dysfunction, which may increase the risk of cardiovascular disease.3 Therefore, recognizing the long-term impact of ARV exposure in young adults infected with HIV in early childhood is of great importance.
Insights into the complications associated with long-term ARV exposure may promote the development of preventive strategies to optimize health outcomes and reduce the risk for cardiometabolic comorbidities in this unique group of individuals with lifelong HIV.
PLWH (n = 70) who completed at least one evaluation were included in cross-sectional comparison with healthy volunteers (n = 47) who were similar in age, sex, race, and ethnicity distributions. Participant demographics and clinical characteristics at their last follow-up are displayed in Table 1. 50% Black, 38% white, 41% male. Of the PLWH, 54% (38/70) had HIV RNA <50 copies/mL and the median (IQR) ARV exposure was 16.2 years (9.0-20.7) at the last follow-up. Of the PLWH for whom nadir CD4 T-cell count was available, 49% (25/51) had a nadir <200 cells/mm3.
PLWH had significantly lower HDL-c and higher diastolic blood pressure, fasting insulin, HOMA-IR, and triglyceride levels relative to the control group (Table 1). The prevalence of hypertriglyceridemia (17% vs. 4%; P = 0.03) and insulin resistance (35% vs. 11%; P = 0.002) were also significantly higher compared with healthy controls. The 2 groups were similar regarding systolic blood pressure, fasting glucose, total cholesterol, and LDL-c. Metabolic syndrome was more common among PLWH, although this difference was not statistically significant (13% vs. 4%; P = 0.1).
PLWH were significantly shorter, although weight and BMI were not significantly different relative to the control group. The prevalence ofobesity (PLWH 20% vs. control 17%) and overweight (PLWH 47% vs. control 51%) in the cross-sectional cohort also did not differ significantly between groups (P > 0.05). The waist to hip ratio and trunk to limb fat ratio were significantly higher in PLWH relative to controls. The individual components of each ratio, namely, waist and hip circumferences as well as trunk and limb fat, were not significantly different between the 2 groups.
Table 2 presents the correlations between measures of body composition and cumulative ARV exposure by class and individual agent among PLWH. There were modest positive correlations between waist to hip ratio and cumulative exposure to NRTIs, non-NRTIs, and PIs. The trunk to limb fat ratio was positively correlated with cumulative NRTI exposure. Neither waist to hip nor trunk to limb fat ratios were associated with cumulative exposure to integrase strand transfer inhibitors. Analyses within each medication class further revealed that waist to hip ratio was positively correlated with cumulative exposure to tenofovir disoproxil fumarate, nevirapine, and ritonavir, whereas trunk to limb fat ratio was positively correlated with stavudine, tenofovir, and nelfinavir. The complete list of individual agents and the median duration of exposures for each agent may be found in Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B748.
Longitudinal Follow-Up of PLWH
The median duration of follow-up was 7 years (IQR 5-10 years) for the subset of PLWH (n = 40) who completed at least 2 DEXA scans and anthropometric measurements. The mean differences over the follow-up period are presented in Table 3. Total CD4 count and rates of viral suppression did not change significantly during follow-up. Only HDL-c significantly increased while there were no significant changes in total cholesterol, LDL-c, triglycerides, blood pressure, insulin, or HOMA-IR. During the course of follow-up, 10% (4/40) of PLWH received antihypertensive medications and 20% (8/40) received lipid-lowering medications. The median duration of ARV exposure during follow-up by class and individual agents are included in Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B748.
Both waist to hip ratio and trunk to limb fat ratio significantly increased from first assessment to last follow-up, along with their individual components: waist circumference, hip circumference, trunk fat, and limb fat. There was a mean (SD) annual increase of 1.24 (1.20) cm for waist circumference, 0.004 (0.01) for waist to hip ratio, and 0.02 (0.04) for trunk to limb fat ratio. The change in duration of general classes of ARVs during follow-up was not significantly related to changes in either waist to hip or trunk to limb fat ratios. However, longer exposure to specific agents throughout follow-up correlated with body composition changes. The increase in waist to hip ratio was positively correlated with greater increase in exposure to darunavir (r = 0.36; P = 0.02). The increase in trunk to limb fat ratio was positively correlated with greater increase in exposure to didanosine (r = 0.39; P = 0.01) and stavudine (r = 0.40; P = 0.01). There was also a significant inverse correlation between the increases in trunk to limb fat ratio and longer exposure to emtricitabine (r = -0.33; P = 0.04) during follow-up, but not with tenofovir DF (r = -0.22; P = 0.17). Each of the statistically significant correlations remained significant after adjusting for the duration of follow-up in a multivariate regression (data not shown).
Although metabolic parameters remained relatively stable over time, the increase in waist to hip ratio was positively correlated with the change in log-transformed triglyceride (r = 0.35; P = 0.03, Fig. 1) and remained significant after a multivariate regression controlling for follow-up duration. Changes in HOMA-IR were not correlated with changes in either waist to hip ratio (r = 0.23, P = 0.18) or trunk to limb fat ratio (r = 0.19, P = 0.26). The observed changes in BMI were not statistically associated with changes in the duration of ARV agents. There were considerable increases in the prevalence of overweight 27.5% to 52.5% and obesity 12.5% to 25% during the follow-up period.
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Associations Between Central Obesity and Lifelong Antiviral Therapy in Adults Living With HIV Acquired From Early Childhood
Sahagun, Seynt Jiro BAa; Yeramosu, Teja BAa; Purdy, Julia B. MSN, CRNPb; Reynolds, James C. MDc; Hadigan, Colleen M. MD, MPHa
Abstract
Background:
Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study explores changes in body fat distribution in relation to ARV exposure.
Methods:
We conducted a prospective study of adults with perinatal HIV (n = 70) using dual-energy X-ray absorptiometry and standard anthropometrics. Trunk to limb fat ratio and waist to hip ratio were compared cross-sectionally to 47 matched controls. Furthermore, changes in body composition and ARV exposure were evaluated longitudinally in a subset of 40 PLWH with a median follow-up of 7 years.
Results:
Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P < 0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = -0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).
Conclusion:
This study presents strong evidence for persistent and worsening central adiposity in young adults with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.
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