Kristine M. Erlandson

Association of Functional Impairment with Inflammation and Immune Activation in HIV Type 1–Infected Adults Receiving Effective Antiretroviral Therapy

BACKGROUND The relationships of inflammation, immune activation, and immunosenescence markers with functional impairment in aging human immunodeficiency virus type 1 (HIV-1)-infected persons are unknown. METHODS HIV-infected persons who were aged 45-65 years, had a plasma HIV-1 RNA load of <48 copies/mL, and were receiving antiretroviral therapy underwent standardized functional testing. In a nested case-control analysis, low-functioning cases were matched (1:1-2) by age, sex, and HIV-1 diagnosis date to high-functioning controls. Markers of inflammation, T-cell activation, microbial translocation, immunosenescence, and immune recovery were used to estimate functional status in conditional logistic regression. Primary analyses were adjusted for CD4(+) T-cell count, smoking, and hepatitis. RESULTS Thirty-one low-functioning cases were compared to 49 high-functioning controls. After statistical adjustment, lower proportions of CD4(+) T cells and higher proportion of CD8(+) T cells, higher CD38/HLA-DR expression on CD8(+) T cells, and higher interleukin-6 were associated with a significantly greater odds of low functional status (odds ratio, ≥ 1.1 for all analyses; P ≤ .03). Other inflammatory, senescence, and microbial translocation markers were not significantly different (P ≥ .11 for all analyses) between low-functioning and high-functioning groups. CONCLUSIONS Functional impairment during successful antiretroviral therapy was associated with higher CD8(+) T-cell activation and interleukin 6 levels. Interventions to decrease immune activation and inflammation should be evaluated for their effects on physical function and frailty.

Risk factors for falls in HIV-infected persons

Background:The incidence of and risk factors for falls in HIV-1–infected persons are unknown. Methods:Fall history during the prior 12 months, medical diagnoses, and functional assessments were collected on HIV-infected persons 45–65 years of age receiving effective antiretroviral therapy. Fall risk was evaluated using univariate and multivariate regression analyses. Results:Of 359 subjects, 250 persons (70%) reported no falls, 109 (30%) had ≥1 fall; and 66 (18%) were recurrent fallers. Females, whites, and smokers were more likely to be recurrent fallers (P ⩽ 0.05). HIV-related characteristics including current and nadir CD4 T-cell count, estimated HIV duration, and Veterans Aging Cohort Study Index scores were not predictors of falls (all P ≥ 0.09); didanosine recipients were more likely to be recurrent fallers (P = 0.04). The odds of falling increased 1.7 for each comorbidity and 1.4 for each medication (P < 0.001) and were higher in persons with cardiovascular disease, hypertension, dementia, neuropathy, arthritis, chronic pain, psychiatric disease, frailty, or disability [all odds ratio (OR) ≥ 1.8; P ⩽ 0.05]. Beta-blockers, antidepressants, antipsychotics, sedatives, and opiates were independently associated with falling (all OR ≥ 2.7; P ⩽ 0.01). Female gender, diabetes, antidepressants, sedatives, opiates, didanosine, exhaustion, weight loss, and difficulty with balance were the most significant predictors of falls in logistic regression (all OR ≥ 2.5; P ⩽ 0.05). Conclusions:Middle-aged HIV-infected adults have high fall risk. Multiple comorbidities, medications, and functional impairment were predictive of falls, but surrogate markers of HIV infection or an HIV-specific multimorbidity index were not. Fall risk should be assessed routinely as part of the care of HIV-infected persons.

Functional impairment is associated with low bone and muscle mass among persons aging with HIV infection.

Background:Disability and frailty are associated with osteoporosis, obesity, and sarcopenia. HIV-infected persons have early functional impairment, but the association between body composition and functional impairment is unknown. Methods:HIV-1–infected participants on combination antiretroviral therapy with virologic suppression, aged 45–65 years, had standardized physical function measures. In a nested analysis, 30 low- and 48 high-functioning cases and controls were matched by age, gender, and time since HIV diagnosis. Bone mineral density, fat mass, and lean body mass were assessed by dual-energy x-ray absorptiometry. Odds ratios (ORs) with 95% confidence intervals were obtained from conditional logistic regression. Results:Mean age was 53 years, mean CD4+ lymphocytes 598 cells per microliter, and 96% had plasma HIV-1 RNA <50 copies per milliliter. Low- and high-function subjects had similar CD4+ lymphocyte count and duration and type of antiretroviral therapy. Lower T scores at the hip [OR: 3.8 (1.1 to 12.5)] and lumbar spine [OR: 2.3 (1.1 to 4.5)] and lower lean body mass [OR: 1.1 (1.0 to 1.2)] were associated with significantly greater odds of low function (P ⩽ 0.03). Lower insulin-like growth hormone [IGF-1; OR: 5.0 (1.4 to 20.0)] and IGF-1 binding protein-3 [OR: 3.3 (1.7 to 9.9)] increased the odds of low functional status (P ⩽ 0.02). Fat mass and lower 25-OH vitamin D did not increase the odds of low functional status (P > 0.05). Conclusions:Functional impairment in HIV-1–infected persons on successful antiretroviral therapy is associated with low muscle mass, low bone mineral density, and low IGF-1 and IGF-1 binding protein-3. These characteristics may be a manifestation of early “somatopause” in middle-aged HIV-infected adults.

Comparison of Functional Status Instruments in HIV-Infected Adults on Effective Antiretroviral Therapy

Abstract Background: The best method for assessment of functional status in human immunodeficiency virus type 1 (HIV-1) infected persons is unknown. Objective: We hypothesized that 3 instruments to assess frailty or disability in elderly populations would perform similarly in HIV-1–infected persons. Methods: HIV-infected subjects 45 to 65 years old with plasma HIV-1 RNA <48 copies/mL were classified prospectively as low, moderate, or high function by Frieds frailty phenotype (FFP), the Short Physical Performance Battery (SPPB), and 400-m walk test. Functional instrument agreement was evaluated by weighted kappa statistic, and relationships with demographic or clinical factors were evaluated by odds ratios (OR). Results: There were 359 participants (85% male, mean age 52 years, mean CD4+ lymphocyte count 551 cells/µL) who were evaluated. Three percent to 8% were low, 31% to 51% were moderate, and 42% to 62% were high function. FFP, SPPB, and 400-m walk test had moderate agreement for functional classification (61%-64%; κ = 0.34-0.41). Across instruments, lower reported physical activity (OR ≯ 5.5; P ≤ .005), no current employment (OR ≯ 4.2; P < .02), arthritis (OR ≯ 6.5; P < .02), neurologic disease (OR ≯ 2.6; P < .05), debilitating pain (OR ≯ 5.4; P < .008), psychiatric disease (OR ≯3.1; P < .03), more comorbidities (OR ≯ 3.6; P ≤ .005), and more non-antiretroviral therapy medications (OR ≯ 3.5; P ≤ .01) were associated with lower function. Current CD4 <200 cells/µL was more likely among low-function (11%) than high-function (2%) persons on FFP (P = .04); other HIV-related characteristics were not significantly different (P > .05) between functional categories on any instrument. Conclusions: Moderate functional impairment is common among middle-aged HIV-infected persons, with similar frequencies of impairment detected by 3 instruments. Reduction in comorbid disease, increased physical activity, and improved pain symptom management could reduce functional impairment among persons aging with HIV-infection.

Functional impairment, disability, and frailty in adults aging with HIV-infection

The integration of antiretroviral therapy (i.e., ART) into HIV care has dramatically extended the life expectancy of those living with HIV. However, in comparison to similar HIV-uninfected populations, HIV-infected persons experience an excess of morbidity and mortality with an early onset of aging complications including neurocognitive decline, osteoporosis, impaired physical function, frailty, and falls. Recent consensus guidelines encourage clinicians and researchers to consider functional impairment of HIV-infected adults as a measure to understand the impact of aging across a range of abilities. Despite the importance of assessing function in persons aging with HIV infection, a lack of consistent terminology and standardization of assessment tools has limited the application of functional assessments in clinical or research settings. Herein, we distinguish between different approaches used to assess function, describe what is known about function in the aging HIV population, and consider directions for future research.

Adjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy

Background Non-AIDS conditions such as cardiovascular disease and non-AIDS defining cancers dominate causes of morbidity and mortality among persons with HIV on suppressive combination antiretroviral therapy. Accurate estimates of disease incidence and of risk factors for these conditions are important in planning preventative efforts. Methods With use of medical records, serious non-AIDS events, AIDS events, and causes of death were adjudicated using pre-specified criteria by an Endpoint Review Committee in two large international trials. Rates of serious non-AIDS which include cardiovascular disease, end-stage renal disease, decompensated liver disease, and non-AIDS cancer, and other serious (grade 4) adverse events were determined, overall and by age, over a median follow-up of 4.3 years for 3,570 participants with CD4+ cell count ≥300 cells/mm3 who were taking antiretroviral therapy and had an HIV RNA level ≤500 copies/mL. Cox models were used to examine the effect of age and other baseline factors on risk of a composite outcome of all-cause mortality, AIDS, or serious non-AIDS. Results Five-year Kaplan-Meier estimates of the composite outcome, overall and by age were 8.3% (overall), 3.6% (<40), 8.7% (40–49) and 16.1% (≥50), respectively (p<0.001). In addition to age, smoking and higher levels of interleukin-6 and D-dimer were significant predictors of the composite outcome. The composite outcome was dominated by serious non-AIDS events (overall 65% of 277 participants with a composite event). Most serious non-AIDS events were due to cardiovascular disease and non-AIDS cancers. Conclusions To date, few large studies have carefully collected data on serious non-AIDS outcomes. Thus, reliable estimates of event rates are scarce. Data cited here, from a geographically diverse cohort, will be useful for planning studies of interventions aimed at reducing rates of serious non-AIDS events among people with HIV.

Relationships between Inflammation, Immune Activation and Bone Health among HIV-Infected Adults on Stable Antiretroviral Therapy

Background:The aim was to determine the association between bone health and inflammation, T-cell activation, and monocyte activation among HIV-infected persons on stable antiretroviral therapy. Methods:We performed a cross-sectional analysis of all the subjects enrolling in the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV trial with available skeletal assessments by dual-energy x-ray absorptiometry, inflammation, and immune activation markers. Analyses used were Wilcoxon rank-sum tests, Spearman correlation coefficients, and linear regression. Results:One hundred forty-two subjects were included: 78% men, 69% African American, median age 46.3 years, CD4+ count 604 cells per microliter, and 77% with undetectable HIV-1 RNA. Twenty-three percent had osteopenia/osteoporosis at the hip, and 21% had this at the lumbar spine. Soluble vascular cell adhesion molecule-1 was correlated with hip (r = −0.22) and spine (r = −0.23) bone mineral density (BMD), and bone turnover markers (r = 0.20–0.33; all P < 0.05). No significant correlations were observed between the BMD and T-cell activation (%CD38HLA-DR on CD4+ or CD8+ T cells), monocyte activation (CD14CD16, sCD14, and sCD163), or inflammatory markers [interleukin (IL)-6, tumor necrosis factor-&agr;, highly sensitive C-reactive protein, D-dimer, receptor activator of NF-kB ligand, osteoprotegerin, soluble tumor necrosis factor-RI and II]. In regression models including traditional bone risk factors, hip BMD was associated with age, race, and body mass index; spine BMD was associated with race, family history of hip fracture, trunk fat, tenofovir, and HIV RNA; bone resorption (c-terminal collagen crosslinks) was associated with intracellular adhesion molecule-1 and trunk fat; bone formation (P1NP) was associated with soluble vascular cell adhesion molecule-1, trunk and limb fat (P ⩽ 0.05). Conclusions:Future studies should evaluate the longitudinal association of the adhesion molecules to further elucidate potential contributory mechanisms of bone loss among HIV-infected persons on stable antiretroviral therapy.

Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density.

Objective:To compare the effect that initiating different antiretroviral therapy (ART) regimens has on weight, BMI, and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD). Methods:A5224s was a sub-study of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir–lamivudine (ABC/3TC) or tenofovir DF–emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir–ritonavir (ATV/r). All participants underwent dual-energy absorptiometry (DXA) and abdominal computed tomography for body composition. Analyses used two-sample t-tests and linear regression. Results:A5224s included 269 participants: 85% men, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/ml, and CD4+ cell count 233 cells/&mgr;l. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks postrandomization (all P < 0.001). Assignment to ATV/r (vs. EFV) resulted in significantly greater weight (mean difference 3.35 kg) and BMI gain (0.88 kg/m2; both P = 0.02), but not LBM (0.67 kg; P = 0.15), whereas ABC/3TC and TDF/FTC were not significantly different (P ≥ 0.10). In multivariable analysis, only lower baseline CD4+ cell count and higher HIV-1 RNA were associated with greater increase in weight, BMI, or LBM. In multivariable analyses, increased LBM was associated with an increased hip BMD. Conclusion:ABC/3TC vs. TDF/FTC did not differ in change in weight, BMI, or LBM; ATV/r vs. EFV resulted in greater weight and BMI gain but not LBM. A positive association between increased LBM and increased hip BMD should be further investigated through prospective interventional studies to verify the impact of increased LBM on hip BMD.

Rosuvastatin Worsens Insulin Resistance in HIV-Infected Adults on Antiretroviral Therapy

BACKGROUND Statins are associated with increased diabetes risk in large, human immunodeficiency virus (HIV)-uninfected cohorts; the impact of statins on insulin resistance or diabetes in HIV-infected persons has not been assessed within a randomized controlled study. METHODS HIV-infected participants on stable antiretroviral therapy with a low-density lipoprotein cholesterol level of ≤130 mg/dL and heightened immune activation or inflammation were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Fasting serum glucose, insulin, and hemoglobin A1C (HgbA1C) were measured; insulin resistance was estimated by calculating the homeostatic model assessment of insulin resistance (HOMA-IR); and a 2-hour oral glucose tolerance test was administered. RESULTS Seventy-two participants were randomized to rosuvastatin therapy and 75 to placebo. Increases in fasting glucose were observed within both groups but were not different between study arms (P = .115); changes in glucose tolerance and HgbA1C did not differ between study arms (P = .920 and P = .650, respectively). Criteria for diabetes were met by 1 participant in the rosuvastatin and 3 in the placebo arm by week 96. Compared with placebo, rosuvastatin therapy was associated with significantly greater increases in insulin and HOMA-IR (P = .008 and P = .004, respectively). CONCLUSIONS We detected a significant worsening in insulin resistance and an increase in the proportion of participants with impaired fasting glucose but not a clinical diagnosis of diabetes in the rosuvastatin arm. Our findings suggest that prescription of statin therapy should be accompanied by a careful consideration of the risks and benefits, particularly in patients with lower cardiovascular disease risk. CLINICAL TRIALS REGISTRATION NCT01218802.

Impact of randomized antiretroviral therapy initiation on glucose metabolism.

Objective:Prior studies have found that early HIV protease inhibitors contribute to glucose dysregulation. Few randomized trials have evaluated glucose indices in antiretroviral-naive individuals on newer antiretroviral therapy (ART). Methods:A5224s was a substudy of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). Analyses used two-sample t-tests, Spearman correlation coefficients and linear regression. Results:A5224s included 269 nondiabetic individuals: 85% men, 47% white non-Hispanic, baseline median age 38 years, HIV-1 RNA 4.6 log10 copies/ml and CD4+ cell count 233 cells/&mgr;l. Overall, significant 96-week increases occurred in fasting glucose, insulin and the homeostatic model assessment of insulin resistance (HOMA-IR), P ⩽ 0.004. Assignment to EFV (versus ATV/r) resulted in significantly greater glucose increase [mean difference 4.4; 95% confidence interval (CI) 1.3, 7.5 mg/dl; P = 0.006] but not insulin or HOMA-IR (P ≥ 0.72). Glucose indices were not significantly different between ABC/3TC and TDF/FTC arms, P ≥ 0.18. Significant correlations were detected between changes in glucose indices and changes in BMI; all r ≥ 0.23, P ⩽ 0.001. In multivariable analyses, in addition to the EFV effect, higher baseline HIV-1 RNA and greater BMI change were significant independent factors associated with greater glucose increase. Conclusion:Changes in glucose metabolism were not significantly different between TDF/FTC and ABC/3TC-based regimens. A small but significantly greater increase in glucose was observed in those assigned to EFV. As glucose dysregulation may increase with time on ART, longer term studies will be needed to further clarify the clinical significance of these findings.