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ObjectiveWhether HIV modifies the relationship of serum lipids with coronary atherosclerosis and coronary plaque subtypes is uncertain. We examined the associations between traditional lipids and coronary atherosclerosis among HIV-infected (HIV+) and HIV-uninfected (HIV-) men.DesignThe Multicenter AIDS Cohort Study is an observational cohort with a total of 429 HIV+ and 303 HIV- men who had non-contrast cardiac computed tomography performed to measure coronary artery calcium and coronary computed tomography angiography to measure coronary stenosis, coronary plaque presence, and composition.MethodsWe used multivariable adjusted prevalence ratios to examine the relationship between the SD difference in each lipid parameter and coronary atherosclerosis.ResultsTotal cholesterol (TC)/HDL-cholesterol had the strongest associations with coronary atherosclerosis regardless of HIV status. Overall, lipid parameters were most strongly associated with the presence of mixed plaque, stenosis more than 50%, and coronary artery calcium for both HIV+ and HIV- men. HIV+ men had similar, but weaker associations, between lipid parameters and coronary atherosclerosis compared with HIV- men. The strongest association was between the TC/HDL-cholesterol and stenosis more than 50% for both HIV+ [prevalence ratios 1.25 per SD (95% confidence interval 1.07-1.43)] and HIV- men [prevalence ratios 1.46 per SD (95% confidence interval 1.08-1.85)].ConclusionThe associations between lipids and coronary atherosclerosis tended to be weaker for HIV+ compared with HIV- men, although TC/HDL had the strongest association for both HIV+ and HIV- men. A weaker association between lipid levels and coronary atherosclerosis for HIV+ men may contribute to the decreased discrimination of cardiovascular disease risk observed in HIV+ individuals.

OBJECTIVES: Urinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity. DESIGN: This observational study included 198 HIV-infected participants from the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study, who initiated TDF between 2009 and 2015 and had urine samples collected at baseline before and after TDF initiation. METHODS: We used linear mixed effects models controlling for urine creatinine and time on TDF to evaluate the effects of TDF initiation on changes in fourteen urinary biomarkers. RESULTS: Within 1 year after TDF initiation, concentrations of trefoil factor 3 (+78%; 95% CI: +38%, +129%), alpha-1 microglobulin (α1m) (+32%; 95% CI: +13%, 55%), clusterin (+21%; 95% CI: +6%, +38%), uromodulin (+19%; 95% CI: +4, +36%), and kidney injury molecule-1 (KIM-1) (+13%; 95% CI: +1%, +26%) significantly increased, whereas interleukin-18 (IL-18) significantly decreased (−13%, 95% CI: −7%, −25%). Subsequent to the first year of TDF use, biomarker concentrations stabilized, and these changes were not statistically significant. When stratifying by baseline viremia (HIV-1 RNA < vs. ≥ 80 copies/mL), concentration changes for most biomarkers during the first year of TDF use were greater among aviremic versus viremic participants, with significant differences in α1m (+80% vs. +22%), KIM-1 (+43% vs. +10%), beta-2 microglobulin (+83% vs. −10%), YKL-40 (+33% vs. −5%), and IL-18 (+20% vs. −27%). CONCLUSIONS: TDF initiation was associated with substantial changes in urinary biomarkers of kidney injury within the first year of use, particularly among aviremic participants. A urinary biomarker panel may be a clinically useful tool to detect and monitor the heterogeneous effects of TDF on the kidney.

OBJECTIVES HIV infection is associated with increased prevalence of subclinical coronary plaque. The extent to which such plaque reflects effects of HIV infection or effects of long-term antiretroviral therapy (ART) use remains unclear and was the goal of this analysis. DESIGN AND METHODS We compared the prevalence and extent of coronary plaque and stenosis between users of specific ART drugs or drug classes using coronary computed tomography (CT) among HIV-infected men in the Multicenter AIDS Cohort Study. To account for time-dependent confounders, including cardiovascular disease risk factors and time-varying reasons for using specific treatments, we conducted fully adjusted logistic and linear models with inverse probability of treatment weighting. RESULTS There were 618 men who underwent noncontrast coronary CT; 450 also underwent coronary CT angiography. At the time of scanning, 81% had undetectable plasma HIV RNA. In fully adjusted models, cumulative use of zidovudine, abacavir, darunavir, and protease inhibitors as a drug class were inconsistently associated with specific forms of plaque presence or extent. CONCLUSION Among virally suppressed HIV-infected men with extensive ART exposure, no consistent associations between use of specific ART drugs and both subclinical coronary plaque presence and extent were apparent. Our findings support the hypothesis that, among virally suppressed persons, type of ART used is not in general a major determinant of subclinical coronary plaque risk.

Objective To study cardiovascular disease risk score utility, we compared the association between Framingham Risk Score (FRS)/pooled cohort equation (PCE) categories and coronary artery plaque presence by HIV serostatus and evaluated whether D : A : D risk category more accurately identifies plaque in HIV-infected men. Design Cross-sectional analysis within a substudy of the Multicenter AIDS Cohort Study. Methods Cardiac computed tomography was performed to assess coronary plaque. We evaluated the association of plaque with increasing cardiovascular disease risk score category, stratified by HIV serostatus, using logistic regression. Receiver operating characteristic curves compared the discrimination of the scores for plaque by HIV serostatus. The sensitivity and specificity of the risk scores were compared in HIV-infected men. Results The risk score category - plaque associations were stronger among HIV-uninfected men than HIV-infected men, except for noncalcified plaque. For example, the odds of coronary artery calcium more than 0 were 7.03 (95% confidence interval 4.21, 11.76) times greater among men in the PCE high-risk versus low-risk category among HIV-uninfected men, compared with just 3.13 (95% confidence interval 2.13, 4.61) times greater among men in the high-risk versus low-risk category among HIV-infected men. Among HIV-infected men, high-risk category by PCE identified the greatest percentage of men with plaque/stenosis, but with lower specificity than D : A : D and FRS. The prevalence of coronary artery calcium more than 0 among men in the PCE low-risk category was 26.5% (HIV-uninfected men) and 36.0% (HIV-infected men). Conclusions FRS and PCE categories associate with plaque burden better in HIV-uninfected men. No risk score delivered both high sensitivity and specificity among HIV-infected men.

Objective: Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and antiretroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine whether HIV infection is associated with greater epicardial fat and whether epicardial fat is associated with subclinical coronary atherosclerosis. Design: We studied 579 HIV-infected and 353 HIV-uninfected men aged 40–70 years with noncontrast computed tomography to measure epicardial adipose tissue (EAT) volume and coronary artery calcium (CAC). Total plaque score (TPS) and plaque subtypes (noncalcified, calcified, and mixed) were measured by coronary computed tomography angiography in 706 men. Methods: We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race, and serostatus and with additional cardiovascular risk factors and tested for modifying effects of HIV serostatus. Results: HIV-infected men had greater EAT than HIV-uninfected men (P ¼ 0.001). EAT was positively associated with duration of antiretroviral therapy (P ¼ 0.02), specifically azidothymidine (P < 0.05). EAT was associated with presence of any coronary artery plaque (P ¼ 0.006) and noncalcified plaque (P ¼ 0.001), adjusting for age, race, serostatus, and cardiovascular risk factors. Among men with CAC, EAT was associated with CAC extent (P ¼ 0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque. Conclusion: Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV. 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2014, 28:1635–1644

Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of HAART. The impact of CH-B on long-term HAART outcomes has not been fully characterized.To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study were retrospectively analyzed. Patients were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS-defining illnesses, CD4 cell rise, and HIV suppression was assessed using regression analysis.Of 816 men followed for a median of 7 years on HAART, 350 were never hepatitis B virus (HBV) infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death [8.3/1000 person-years (PYs)]. It was highest in those with CH-B (17/1000 PYs, 95% confidence interval 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% confidence interval 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared with those never infected (P = 0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted hazard ratio 4.1, P = 0.04). There was no significant difference in AIDS-defining events, HIV RNA suppression, and CD4 cell increase.In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 cell increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.

Evidence regarding the effect of tuberculosis disease (TB) on HIV disease progression at the population level remains inconclusive. We estimated the effect of incident TB on time to acquired immunodeficiency syndrome (AIDS)-related death, using a marginal structural Cox model. Between 1984 and 2005, 2,882 HIV-infected men in the Multicenter AIDS Cohort Study contributed 21,914 person-years while followed for a median of 5.4 years. At study entry, the median CD4 cell count and HIV-1 RNA viral load were 533 cells/mm3 (interquartile range [IQR], 365 – 737) and 12,953 copies/ml (IQR, 2,453 – 48,540), respectively. This study was performed in a setting with a modest exposure to HAART; 8,295 of 23,801 (35%) person-years were followed during the HAART era. Fifteen men incurred incident TB, yielding a TB incidence of 7 (95% confidence interval [CI]: 4, 14) per 10,000 person-years, and 1,072 died of AIDS-related causes. Accounting for potential confounders, including CD4 cell count and viral load, the hazard of AIDS-related death was 2.4 times larger for the person-time with TB, compared to the person-time without TB (95% CI: 1.2, 4.7). Results underscore the importance of avoiding TB by using preventive interventions, such as treatment of latent TB infection, particularly in populations with a large prevalence of HIV/TB co-infected individuals.

BACKGROUND The relative contributions of the different classes of antiretroviral therapy (ART), HIV infection per se, and aging to body shape changes in HIV-infected patients have not been clearly defined in longitudinal studies. METHODS Since September 1999, men enrolled in the Multicenter AIDS Cohort Study have undergone measurements of body mass index (BMI) and body circumferences at each semi-annual visit. The effect of HIV-serostatus and cumulative exposure to the three major ART classes on changes in anthropomorphic measurements occurring between 1999 and 2004 among HIV-infected and HIV-uninfected men were determined using linear mixed effects regression models. RESULTS At baseline, average BMI and circumference measurements were greater in HIV-uninfected men (n = 392) than HIV-infected men (n = 661) (BMI, 27.3 versus 25.3 kg/m; waist, 96.4 versus 90.2 cm; hip 101.3 versus 95 cm, thigh 54.1 versus 50.8 cm; arm 33.3 versus 31.7 cm, P < 0.001 for each comparison). Cumulative nucleoside reverse transcriptase inhibitor (NRTI) exposure, but not protease inhibitor or non-nucleoside reverse transcriptase inhibitor exposure, was associated with statistically significant changes in BMI (-0.11 +/- 0.04 kg/m per year) and in circumferences of waist (-0.27 +/- 0.07 cm/year), hip (-0.24 +/- 0.05 cm/year), and thigh (-0.16 +/- 0.03 cm/year) over the 5 years of follow-up. Independent of ART exposure, HIV-infected men had a more rapid increase in waist circumference over the study interval than did the HIV-uninfected men (difference 0.33 +/- 0.15 cm/year, P = 0.02). CONCLUSION Cumulative NRTI therapy was associated with longitudinal decreases in body circumference measurements, whereas HIV-serostatus was associated with increases in waist circumference independent of ART.

Objective: We conducted a randomized, multi-site, controlled trial of a cognitive-behavioral adherence intervention for patients initiating or changing an antiretroviral (ART) regimen. Design: A 3 x 2 factorial design was used with the primary randomization assigning patients (1 : 1 : 1) to one of two adherence interventions or usual care. Methods: The five-session adherence interventions consisted of cognitive-behavioral and motivational components, with or without a 2-week pre-treatment placebo practice trial. Intent-to-treat analysis used probability weights and regression tree analysis to account for missing data. Results: A total of 230 patients were randomized; 199 started ART, of whom 74% completed the 48-week study. Electronic monitored adherence outcomes between the two intervention groups did not differ significantly and were thus pooled in analyses. At week 4, 82% of intervention patients had taken at least 90% of their prescribed ART doses, compared with 65% of controls (P < 0.01); this group difference dropped to 12% at week 12 (72 versus 60%; P = 0.15) and 11 % at week 24 (66 versus 55%; P = 0.28). Mean adherence in the intervention group was significantly higher than the control group at week 24 (89 versus 81%; P < 0.05) only. There were no group differences with respect to HIV-1 RNA throughout the study. Conclusions: The effects of the cognitive-behavioral intervention on adherence were modest and transient, and no effects were observed on viral load or CD4 cell count. More robust effects may require a more intense intervention that combines ongoing adherence monitoring and individualized intervention 'dosage' that matches the need and performance of each patient.

OBJECTIVE To evaluate the clinical significance of hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI). DESIGN Analysis of a prospective clinical trial cohort. PATIENTS NNRTI-naive patients failing a stable antiretroviral regimen. MEASUREMENTS HIV phenotype, HIV RNA, and CD4 cell counts were prospectively collected after patients changed to a new regimen. Hypersusceptibility to NNRTI was defined as a fold-change (FC) in IC50 (inhibitory concentration of 50%) of < 0.4. RESULTS The 177 patients had a mean HIV RNA of 4.1 log10 copies/ml, CD4 cell count of 322 x 10(6) cells/l and 41 months of prior antiretroviral treatment. Hypersusceptibility to one or more NNRTI was present in 29%. Both longer duration and reduced susceptibility to nucleoside reverse transcriptase inhibitors were associated with efavirenz hypersusceptibility (P < 0.05). NNRTI-containing regimens were initiated in 106 patients at baseline. The mean change in log HIV RNA after 6 months was greater for patients with hypersusceptibility (-1.2 log10 copies/ml; n = 21) than in patients without (-0.8 log10 copies/ml; n = 77) (P = 0.016). Differences persisted to month 12 (P = 0.023). Multiple linear regression models confirmed that hypersusceptibility to NNRTI was a significant independent predictor of the magnitude of early (months 1-4) HIV RNA reduction, after accounting for the baseline HIV RNA and the number of drugs to which the patient's virus was susceptible (P < 0.02). CD4 cell increases (months 4-10) were 28- 60 x 10(6) cells/l greater in patients with hypersusceptible virus (P < or = 0.1). CONCLUSION NNRTI hypersusceptibility occurred in more than 20% of nucleoside-experienced patients and was associated with greater reduction of HIV RNA and increase in CD4 cells.