The term metabolic syndrome (MetS) reflects the concurrence of risk factors for atherosclerosis and microvascular disease and includes obesity, glucose intolerance, hypertension, and dyslipidemias. The prevalence of MetS in HIV-infected (HIV-positive) patients ranges from 25 to 96% depending on definition used [1,2].
HIV-associated sensory neuropathy (HIV-SN) is caused by either HIV infection or several HAART medications, including dideoxynucleoside reverse transcriptase inhibitors (d-drugs), and is among the most common neurological complications of HIV . HIV-SN patients present with numbness, paresthesias, and/or pain causing decreased mobility . Prior to HAART, the risk and severity of HIV-SN correlated with advanced immunosupression (lower CD4 cell count) and increased plasma HIV viral loads . HAART has improved immune function, suppressed HIV replication, and decreased the incidence, but not the prevalence of HIV-SN [6–8]. Continued persistence suggests other contributing causes .
In HIV-uninfected (HIV-negative) individuals, sensory neuropathy is associated with MetS components [9,10]. We evaluated whether MetS, or its components, predisposes individuals to HIV-SN within a multicenter, prospective, cross-sectional study [CNS HIV Antiretroviral Therapy Effects Research (CHARTER)] investigating the effects of antiretroviral therapy in the nervous system.
HIV-positive patients for CHARTER were recruited from six North American academic HIV-positive clinics. The Institutional Review Boards at each site approved all research. All patients completed a cross-sectional evaluation consisting of comprehensive neuromedical assessments, phlebotomy, and lumbar puncture. From this cohort, metabolic substudy patients were selected.
At the time of analysis, 1556 HIV-positive patients were enrolled and examined cross-sectionally within CHARTER from June 2006 to September 2007. Informed consent was received from each participant prior to enrollment. Those meeting criteria for the metabolic subgroup (n = 130) had a fasting blood draw and neuromedical examination.
Characterization of HIV infection
Blood CD4 cell counts were measured by flow cytometry. HIV RNA levels were quantified in plasma and cerebrospinal fluid (CSF) by reverse transcriptase-polymerase chain reaction (Amplicor; Roche Diagnostic Systems, Indianapolis, Indiana, USA) using an ultrasensitive assay (lower quantification limit < 50 copies/ml). HIV RNA levels were log10 transformed and analyzed continuously and categorically, based on whether or not the value was below the limit of the assay (undetectable vs. detectable).
Details of past and current antiretroviral usage were captured by combined self-report and interview questionnaires. Data collected included usage dates, dose, and schedule for each antiretroviral drug. Antiretroviral usage was categorized as currently on, past use, or never used with particular emphasis on dideoynucleoside antiretroviral drugs (d-drugs), such as stavudine and didanosine. These drugs can be associated with HIV-SN. Nadir CD4 cell count since HIV infection was self-reported.
HIV-associated sensory neuropathy definition
Trained personnel completed targeted, standardized neurological examinations to diagnose HIV-SN. Clinical signs associated with HIV-SN included diminished vibration sense in great toes, decreased or inability to discriminate between sharp and dull sensation in the feet, and absent or weakened bilateral ankle reflexes. HIV-SN diagnosis was based on presence of at least one sign bilaterally and symmetrically . Self-reported symptoms of HIV-SN (including loss of sensation, hyperalgesia, tingling, pain, or bilateral burning in the feet) were recorded but not required for HIV-SN diagnosis.
Metabolic syndrome definition
MetS was defined if at least three of the following criteria from the National Cholesterol Education Program Adult Treatment Panel III were present : elevated mean arterial pressure (MAP) of at least 100 mmHg; elevated fasting triglycerides (TRGs) (≥150 mg/dl); reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dl (male patients) or <50 mg/dl (female patients)]; obesity with elevated body mass index (BMI) (>25 kg/m2); elevated fasting plasma glucose (GLU) (≥100 mg/dl) .
Clinical and metabolic laboratory measures
All metabolic substudy participants endorsed abstaining from food and drink for 8 h prior to their blood draw. Blood samples for glucose measurement were collected in serum separator tubes. After clotting, serum was separated and sent to each institution's laboratory for glucose, total cholesterol, TRGs, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) measures. MetS components were dichotomized as abnormal or normal. All BP measurements were obtained using automated calibrated mercury sphygmomanometers and appropriate cuff sizes. Systolic and diastolic BP measures were obtained from seated patients [13,14]. Height and weight for calculating BMI were measured at entry. Diagnosis of diabetes mellitus type 2 and use of diabetes medication were self-reported.
Univariate analyses assessed for possible differences in prevalence of MetS within HIV-positive patients with and without sensory neuropathy using a χ2 test. Risk factors including demographic characteristics (age and sex), markers of HIV disease progression (current CD4 cell counts, CD4 nadir, length of HIV infection, plasma and CSF viral load), antiretroviral characteristics (d-drug and protease inhibitor use, HAART duration), diabetes, and hepatitis C coinfection were evaluated for differences between those with and without HIV-SN using either t-tests or χ2 tests. Logistic regression was used to determine the unadjusted odds ratios (ORs) for each independent variable as a predictor for HIV-SN. Adjusted ORs were determined after correcting for age, current CD4 cell count, length of infection, d-drug, and protease inhibitor use. All MetS components were logarithmically transformed to reduce skewness and equalize variance. A univariate analysis for each MetS component and HIV-SN was assessed for the metabolic subgroup and larger cohort. All analyses were performed using JMP statistical package (V6.0; SAS Institute, Inc., Cary, North Carolina, USA).
Comparison of participants with and without HIV-associated sensory neuropathy
The cohort was primarily male (85%) ranging in age from 20 to 67-year-olds with HIV-SN participants tending to be older (Table 1). Most patients were on a stable HAART regimen (72%) and were immune reconstituted as evidenced by a high current median CD4 cell count (513 cells/μl) and a median plasma viral load below limits of detection in both the CSF and plasma (50 or 1.7 log10 copies/ml), despite a relatively low median nadir CD4 cell count (137 cells/μl).
Risk factors of HIV-associated sensory neuropathy
Older age (OR = 1.06, P < 0.001, 95% CI 1.05–1.15), increased duration of infection (OR = 1.11, P < 0.001, 95% CI 1.07–1.25), and lower CD4 nadir (OR = 1.01, P = 0.04, 95% CI 1.00–1.01) significantly increased the risk of HIV-SN. Likewise, past d-drug (OR = 1.71, P < 0.01, 95% CI 1.30–6.68) and protease inhibitor (OR = 2.63, P < 0.01, 95% CI 1.23–5.52) use were associated with HIV-SN. Neither hepatitis C coinfection (n = 17) nor self-reported type 2 diabetes mellitus (n = 11) was associated with HIV-SN.
Metabolic syndrome and HIV-associated sensory neuropathy were unrelated
Both MetS and HIV-SN were prevalent in the metabolic substudy group. Overall, approximately 32% (42/130) of patients met MetS criteria. HIV-SN was diagnosed in 55% of the cohort (71/130). However, MetS was not associated with HIV-SN (P = 0.69).
After controlling for possible HIV-associated sensory neuropathy risk factors, metabolic syndrome remained unrelated to HIV-associated sensory neuropathy
We assessed four potential HIV risk factors that could confound the relationship between MetS and HIV-SN (Table 1): demographic characteristics, HIV disease status, antiretrovirals, and aspects of past medical history. After controlling for age, CD4 current, length of HIV infection, d-drug use ever, and past protease inhibitor use in a multivariate logistic regression model, MetS remained unrelated to HIV-associated HIV-SN (P = 0.72).
Of the metabolic syndrome components, only elevated triglycerides increased the risk for HIV-associated sensory neuropathy
As MetS is a constellation of disorders, we assessed the role of each MetS component in HIV-SN. Univariate analysis using each factor as a continuous variable revealed that only elevated TRG was associated with HIV-SN (P = 0.009, Table 2). From the larger CHARTER cohort who had either fasting or nonfasting TRG measures (n = 1518 patients), elevated TRGs were associated with HIV-SN (OR = 1.30, P = 0.01, 95% CI 1.06–1.59). However, no significant association occurred between age and TRG for the two groups.
Self-reported diabetes mellitus type 2 was a risk factor in the larger CNS HIV Antiretroviral Therapy Effects Research cohort
As the total number of patients with diabetes mellitus type 2 was low (11/130) in the metabolic substudy group, we examined the association of self-reported diabetes mellitus type 2 and HIV-SN in the CHARTER cohort. Diabetes mellitus type 2 was associated with increased risk of HIV-SN (OR = 1.41, P < 0.01, 95% CI 1.08–1.81).
MetS was not associated with HIV-SN in this cohort of HIV-positive patients from multiple institutions (P = 0.72). However, two MetS components, diabetes mellitus type 2 and elevated TRG, increased the risk of HIV-SN. Specifically, elevated TRG (>150 mg/dl) conferred a 30% greater risk of HIV-SN, and self-reported diabetes mellitus type 2 conferred a 40% greater risk of HIV-SN. Both factors have been associated with idiopathic sensory neuropathy in HIV-uninfected populations . Without HIV-uninfected controls, we cannot address whether the increased risks of HIV-SN from these MetS components produce an additive or interactive effect with HIV in causing sensory neuropathy.
Other clinical correlates for HIV-SN in this study were similar to those found in previous studies. These risk factors included increased age, low current CD4 cell count, length of HIV infection, and d-drug exposure [4,16,17].
The prevalence of HIV-SN has persisted despite widespread adoption of HAART regimens avoiding d-drugs . This result is possibly due to persisting symptoms after discontinuing d-drugs . This study, similar to earlier analyses, showed that the prevalence of HIV-SN depends on definition used. When electromyographic criteria were applied, the prevalence was low (1.8%) , but if subclinical or asymptomatic neuropathy measures were included, the prevalence was higher (62%) [20,21]. Our observed prevalence of HIV-SN (57%) is similar to the larger CHARTER cohort in which it is nested .
The relationship between diabetes mellitus type 2 and elevated fasting TRGs and sensory neuropathy is similar to that in a study of HIV-uninfected adults . The association with diabetes mellitus type 2 was clearly demonstrated in the larger CHARTER cohort but may have been missed in the metabolic subgroup as a small number of diabetes mellitus type 2 (8%) could lead to an underestimation of HIV-SN prevalence. The effect of TRG on HIV-SN may be complicated by statins used to treat elevated TRGs as these medications may confer an additional risk. Future studies investigating the role of statins in HIV-SN are required.
The relationship between diabetes mellitus type 2 and HIV-SN resembles a similar, but stronger, relationship in the same cohort between diabetes mellitus type 2 and cognitive dysfunction. Diabetic patients had a five-fold increased risk of neurocognitive impairment compared with nondiabetic HIV-positive patients. Median global deficit score (GDS), a measure of each patient's overall cognitive dysfunction, were higher in diabetic patients compared with nondiabetic patients (median GDS = 0.87 vs. 0.13, P < 0.01). Whether the same mechanisms underlie damage in the CNS and peripheral nerves remains unclear.
Limitations of this study are its cross-sectional design and small study population which may have decreased the power to detect the impact of individual MetS components on HIV-SN. Its strengths include the recruitment of HIV-positive patients from multiple institutions across the United States; the assessment of HIV-SN by trained personnel using standardized methods; and thorough accounting for potential confounding factors such as age, HIV infection status, and drug exposures.
These findings illustrate the pathogenic complexity HIV-SN to which both HIV infection and its treatment are known contributors. Additionally, this study shows that diabetes mellitus type 2 and hypertriglyceridemia independently contribute to sensory neuropathy. Although the widespread abandonment of d-drugs in developed countries should decrease the incidence of HIV-SN, the continued use of other HAART drugs causing sensory neuropathy, in particular protease inhibitors, may increase the risk of MetS and help sustain its high prevalence.
The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego, University of Texas, Galveston, University of Washington, Seattle, Washington University, St Louis and is headquartered at the University of California, San Diego. Members of the CHARTER group include Igor Grant, MD (Director); J. Allen McCutchan, MD, Ronald J. Ellis, MD, PhD, Thomas D. Marcotte, PhD (Co-Directors); Donald Franklin, Jr (Center Manager); Neuro-medical Component: Ronald J. Ellis, MD, PhD (Principal Investigator), J. Allen McCutchan, MD, Terry Alexander, RN; Laboratory, Pharmacology and Immunology Component: Scott Letendre, MD (Principal Investigator), Edmund Capparelli, PharmD, Janis Durelle; Neurobehavioral Component: Robert K. Heaton, PhD (Principal Investigator), J. Hampton Atkinson, MD, Steven Paul Woods, PsyD, Matthew Dawson; Virology Component: Joseph K. Wong, MD (Principal Investigator); Imaging Component: Terry Jernigan, PhD (Co-Principal Investigator), Michael J. Taylor, PhD (Co-Principal Investigator), Rebecca Theilmann, PhD; Data Management Unit: Anthony C. Gamst, PhD (Principal Investigator), Clint Cushman; Statistics Unit: Ian Abramson, PhD (Principal Investigator), Christopher Ake, PhD, Florin Vaida, PhD; Protocol Coordinating Component: Thomas D. Marcotte, PhD (Principal Investigator), Rodney von Jaeger, MPH; Johns Hopkins University Site: Justin McArthur (Principal Investigator), Gilbert Mbeo, MBChB; Mount Sinai School of Medicine Site: Susan Morgello, MD (Co-Principal Investigator) and David Simpson, MD (Co-Principal Investigator), Letty Mintz, NP; University of California, San Diego Site: J. Allen McCutchan, MD (Principal Investigator), Susan Ueland, RN; University of Washington, Seattle Site: Ann Collier, MD (Co-Principal Investigator) and Christina Marra, MD (Co-Principal Investigator), Trudy Jones, MN, ARNP; University of Texas, Galveston Site: Benjamin Gelman, MD, PhD (Principal Investigator), Eleanor Heckendorn, RN, BSN; and Washington University, St Louis Site: David Clifford, MD (Principal Investigator), Muhammad Al-Lozi, MD, Mengesha Teshome, MD.
Author contributions: study design was done by B.M.A., D.R., J.M.-B., R.J.E., J.A.M.; statistical analysis was done by B.M.A., F.V., D.R.; drafting of paper was done by B.M.A., D.R., R.J.E., D.M.S., D.B.C., J.C.M., I.G., J.A.M.; revisions of paper were done by B.M.A., F.V., D.R., R.J.E., D.M.S., D.B.C., J.C.M., I.G., J.A.M.
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