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Bone loss and cognitive impairment are common in women living with HIV (WLWH) and are exacerbated by menopause. Bone-derived undercarboxylated osteocalcin (ucOCN) and sclerostin appear to influence cognition. The current study investigated whether the circulating levels of these 2 proteins are associated with cognition in midlife WLWH and demographically similar HIV seronegative women.Plasma samples from women enrolled in a musculoskeletal substudy within the Women's Interagency HIV Study were used to measure ucOCN and sclerostin. A neuropsychological (NP) test battery assessing executive function, processing speed, attention/working memory, learning, memory, verbal fluency, and motor function was administered within 6 months of musculoskeletal enrollment and every 2 years after (1-4 follow-up visits per participant). A series of generalized estimating equations were conducted to examine the association between biomarkers and NP performance at the initial assessment and over time in the total sample and in WLWH only. Primary predictors included biomarkers, time, and biomarker by time interactions. If the interaction terms were not significant, models were re-run without interactions.Neither biomarker predicted changes in NP performance over time in the total sample or in WLWH. ucOCN was positively associated with executive function in the total sample and in WLWH and with motor skills in WLWH. ucOCN was negatively associated with attention/working memory in the total sample. There were no significant associations between sclerostin and NP performance.The current study suggests an association between bone-derived ucOCN and cognition in women with and without HIV infection.

Background Bone mineral density (BMD) loss and fat accumulation are common in people living with HIV (PLWH). The bone-derived hormone, undercarboxylated osteocalcin (ucOCN) regulates fat metabolism. We investigated the relationship between ucOCN change and body fat change among perimenopausal/postmenopausal HIV-seronegative and HIV-seropositive women on long-term antiretrovirals. Methods Perimenopausal and postmenopausal women enrolled in the Women's Interagency HIV Study (WIHS) MSK sub-study underwent trunk and total fat assessment via dual x-ray absorptiometry (DXA) at study enrollment (index visit) and again two years later. Circulating ucOCN and carboxylated osteocalcin (cOCN) were also measured at the index and two-year visits. The correlation between the two-year change in ucOCN and cOCN and change in trunk and total fat was assessed as a function of HIV-serostatus using linear regression modeling. Multivariate linear regression assessed the association between ucOCN and cOCN change and total and trunk fat change after adjusting for sociodemographic variables. Linear regression models restricted to HIV-seropositive women were performed to examine the contributions of HIV specific factors (index CD4 count, viral load, and cART use) on the associations. Results Increased ucOCN over the two-year follow-up was associated with less trunk and total fat accumulation in models adjusting for HIV-serostatus and participants sociodemographics, while there was no association with cOCN and the fat parameters. None of the HIV-specific factors evaluated influenced the association between ucOCN and fat parameters. Conclusion The current study suggests that increases in ucOCN are associated with decreased fat accumulation in HIV-seronegative and HIV-seropositive postmenopausal women on long-term antiretroviral therapy.

In HIV negatives, markers of hemostasis, including D-dimer, factor VIII, plasminogen activator inhibitor-1 antigen (PAI-1), and total protein S are associated with all-cause and cardiovascular disease mortality. In HIV positives, studies of D-dimer and factor VIII with death were limited to short follow-up; associations of PAI-1 and total protein S with death have not been examined. In 674 HIV-infected women from the Women's Interagency HIV Study, markers from the first visit after enrollment were exposures of interest in multivariate analyses of death (AIDS and non-AIDS) in separate models at 5 and 16 years. There were 87 AIDS and 44 non-AIDS deaths at 5 years, and 159 AIDS and 113 non-AIDS deaths at 16 years. An inverse association of total protein S quartiles with non-AIDS deaths was observed at 5 (P trend = 0.002) and 16 years (P trend = 0.02); there was no association with AIDS deaths. The third quartile of PAI-1 was associated with AIDS deaths at 5 [hazard ratio (HR) = 4.0; 95% confidence interval (CI): 1.9 to 8.4] and 16 years (HR = 3.4; 95% CI: 1.9 to 5.9); and with non-AIDS deaths at 5 years (HR = 4.8; 95% CI: 1.6 to 13.9). D-dimer and factor VIII were not associated with AIDS or non-AIDS death at 5 or 16 years. Lower total Protein S was a consistent marker of non-AIDS death. We found no association between D-dimer with AIDS or non-AIDS death, in contrast to previous studies showing increased short-term (

Background Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Women's Interagency HIV Study to explore the hypothesis that compared with HIV-uninfected participants, women with HIV, and, in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity. Methods Nineteen HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ≤ 2600 copies/mL (low viral load) (HIV-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). The CVL antimicrobial activity was also determined. Results Compared to HIV-uninfected participants, HIV-HVL women had higher levels of mucosal but not systemic proinflammatory cytokines and chemokines, higher Nugent scores, and lower Escherichia coli bactericidal activity. In contrast, there were no significant differences between HIV-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1β, MIP-1α, and CCL5 (RANTES) and higher plasma concentrations of MIP-1α. High PVL was associated with higher CVL levels of IL-1β and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking, and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model. Conclusions Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.

BACKGROUND Coinfection with HIV and hepatitis C virus (HCV) is common. HIV infection and treatment are associated with hypercoagulability; thrombosis in HCV is underinvestigated. Proposed markers of hemostasis in HIV include higher D-dimer, Factor VIII%, and plasminogen activator inhibitor-1 (PAI-1) antigen and lower total Protein S% (TPS) but have not been examined in HCV. We assessed the independent association of HCV with these 4 measures of hemostasis in a multicenter, prospective study of HIV: the Women's Interagency HIV Study. METHODS We randomly selected 450 HCV-infected (anti-HCV+ with detectable plasma HCV RNA) and 450 HCV-uninfected (anti-HCV-) women. HCV was the main exposure of interest in regression models. RESULTS Four hundred forty-three HCV+ and 425 HCV- women were included. HCV+ women had higher Factor VIII% (124.4% ± 3.9% vs. 101.8% ± 3.7%, P < 0.001) and lower TPS (75.7% ± 1.1% vs. 84.3% ± 1.1%

Objective To examine condom-use decision making in the context of hypothetical pre-exposure prophylaxsis (PrEP) efficacy among men who have sex with men who use alcohol and other substances during sex. Methods Substance-using men who have sex with men were recruited in 4 US cities for a behavioral intervention trial. Three groups were defined as follows: men who indicated that to not use a condom for receptive/insertive unprotected anal intercourse (UAI) while using PrEP, PrEP would need to be: (1) "almost always or always" effective (high efficacy); (2) effective "at least half the time or more but not almost always or always" (mid-range efficacy corresponding to recent PrEP trial results); (3) effective "less than half the time" (low efficacy). The mid-range efficacy group was compared with the low-efficacy group (as the reference) and to the-high efficacy group (as the reference). Results Among 630 men who never used PrEP, 15.2% were in the mid-range efficacy group for receptive UAI and 34.1% in the mid-range efficacy group for insertive UAI. Scores on difficulty communicating about safer sex while high were significantly higher in the mid-range efficacy group compared with each of the other groups for both receptive and insertive UAI. Men who seemed to be differentiating PrEP use by anal sex role also scored higher on communication difficulties, although scoring lower on condom intentions. Conclusions Communication about safer sex while under the influence of alcohol or other substances and condom intentions are important factors to consider for HIV prevention interventions for PrEP users.

BACKGROUND: This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009. METHODS: Infants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection death and HIV infection or death using Kaplan-Meier analysis. RESULTS: This analysis includes 3126 infants uninfected at birth as follows: 1004 control 1071 ExtNVP and 1051 ExtNVP/ZDV. By 9 months HIV infection rates were 5.0% in ExtNVP 6.0% in ExtNVP/ZDV and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm. CONCLUSIONS: Daily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.

BACKGROUND Opiate use is common in HIV-infected and hepatitis C virus (HCV)-infected individuals, however, its contribution to the risk of diabetes mellitus is not well understood. METHODS Prospective study of 1713 HIV-infected and 652 HIV-uninfected participants from the Women's Interagency HIV Study between October 2000 and March 2006. Diabetes defined as fasting glucose > or =126 mg/dL, self report of diabetes medication use, or confirmed diabetes diagnosis. Opiate use determined using an interviewer-administered questionnaire. Detectable plasma HCV RNA confirmed HCV infection. RESULTS Current opiate users had a higher prevalence of diabetes (15%) than nonusers (10%, P = 0.03), and a higher risk of incident diabetes (adjusted relative hazard: 1.58, 95% confidence interval: 1.01 to 2.46), after controlling for HCV infection, HIV/antiretroviral therapy status, and diabetes risk factors including age, race/ethnicity, family history of diabetes, and body mass index. HCV infection was also an independent risk factor for diabetes (adjusted relative hazard: 1.61, 95% confidence interval: 1.02 to 2.52). HCV-infected women reporting current opiate use had the highest diabetes incidence (4.83 cases per 100 person-years). CONCLUSIONS Among women with or at-risk for HIV, opiate use is associated with increased diabetes risk independently of HCV infection. Diabetic screening should be part of care for opiate users and those infected with HCV.

BACKGROUND: We assessed gastroenteritis (GE) burden in 2 randomized trials conducted in Malawi to reduce postnatal HIV transmission before and after World Health Organization recommendations regarding exclusive breastfeeding for HIV-exposed infants were adopted. The 2 trials were the nevirapine/AZT (NVAZ 2000-2003 with prolonged breastfeeding) and the Postexposure Prophylaxis to the Infant (PEPI 2004-2007 with breastfeeding cessation by 6 months). METHODS: From NVAZ and PEPI trials data GE frequency through age 12 months among HIV-negative exposed infants was evaluated. Overall and GE-related cumulative mortality rates were estimated using Kaplan-Meier curves. RESULTS: The frequency of at least one GE-related hospitalization was greater in PEPI vs. NVAZ after age 6 months (respectively 2.9% vs. 0.1% at 7-9 months and 1.6% vs. 0.2% at 10-12 months P < 0.001). Cumulative GE-related mortality was significantly higher in PEPI than in NVAZ after age 6 months; at ages 9 and 12 months GE-related mortality was 19 and 24 per 1000 infants in PEPI vs. 7 and 12 per 1000 infants in NVAZ (P = 0.0002). CONCLUSIONS: Early weaning was associated with increased risk of severe GE and GE-related mortality among HIV-exposed infants. Strategies are urgently needed which allow longer breastfeeding while reducing the risk of HIV breast milk transmission in resource-limited settings.

Background—The effects of HIV serostatus and combination antiretroviral therapy (cART) on plasma homocysteine (Hcy) are uncertain. Methods—Plasma Hcy was assayed in a cross-sectional study of 249 HIV-infected and 127 HIVuninfected women at the Bronx Women’s Interagency HIV Study site. Results—Mean plasma Hcy was 7.42 ± 2.68 in HIV-infected and 7.18 ± 2.66 µmol/L in HIVuninfected women (P = 0.40). Hyperhomocysteinemia (defined as Hcy > 10 µmol/L) was seen in 16.9% and 13.4 % of HIV-infected and HIV-uninfected women, respectively (P=0.45). Among HIVinfected women, cART use was not associated with Hcy level. Compared to the lowest quartile, women with Hcy in the highest quartile had lower mean serum vitamin B12 and RBC folate levels. In multivariate analysis that did not include micronutrient levels, age, serum creatinine and lower CD4% were significantly associated with plasma Hcy level in HIV-infected women. Conclusions—Plasma Hcy was not associated with HIV serostatus or use of cART in this crosssectional study. Reduced availability of folate cofactors for Hcy remethylation in HIV-infected women with lower folate intake and decreased health status may influence Hcy levels.

Introduction: Previous studies suggest that indicators of central adiposity such as waist-to-hip ratio (WHR) and waist circumference may be altered by HIV infection, antiretroviral treatment, or both. Methods: Waist and hip circumference and body mass index (BMI) were measured among participants of the Women's Interagency HIV Study semiannually from 1999 to 2004. Generalized linear models evaluated longitudinal patterns of these measures and associations with demographic and clinical characteristics. Results: WHR was significantly larger, whereas BMI and waist and hip circumference were significantly smaller at almost all 11 semi-annual visits among 942 HIV-infected women compared with 266 HIV-uninfected women. Among HIV-uninfected women, mean waist and hip circumference and BMI increased over the 5-year study period (waist: +4.1 cm or 4.4%, hip: +3.76 cm or 3.5%, and BMI +2.43 kg/m 2 or 8.2%), whereas WHR remained stable. Among the HIV-infected women, waist and hip circumference, BMI, and WHR did not significantly change. Independent predictors of smaller BMI among HIV-infected women included white race, hepatitis C virus seropositivity, current smoking, higher viral load, and lower CD4 cell count. Independent predictors of larger WHR among HIV-infected women included age, white and other non-African American race, higher CD4 cell count, and protease inhibitor (PI) use. Use of a highly active antiretroviral therapy (HAART) regimen was not an independent predictor of BMI or WHR. Conclusions: HIV-infected women had higher WHRs compared with HIV-uninfected women, despite lower BMIs and waist and hip measurements. BMI and waist and hip circumference increased over 5 years among the HIV-uninfected women but remained stable in the HIV-infected women. Among HIV-infected women, PI use was associated with a larger WHR, although HAART use itself was not appreciably associated with BMI or WHR.

Background: Diabetes mellitus (DM) is more prevalent among patients with HIV infection. Besides protease inhibitors (PIs), other factors may contribute to the development of DM. Objective: To assess characteristics associated with the development of DM in HIV-infected persons. Methods: We conducted a case-control study in an urban HIV clinic among patients with incident DM (49 cases) matched to 2 controls (n = 98) on age ±5 years, race, sex, and length of clinic follow-up. There was a second set of unmatched controls (n = 196). Results: Compared with matched controls, case patients had higher mean body mass index (BMI; 30.0 vs. 25.3 kg/m 2 , matched odds ratio [OR] = 1.20; P < 0.001), higher alanine aminotransferase (ALT; 66 vs. 44 U/L, OR = 1.12 per 10 U/L; P = 0.013), and stronger family history of DM (50% vs. 29%, OR = 3.30; P = 0.009). Hepatitic C virus coinfection and PI use were not significant factors. In unmatched controls, there was no significant difference in age, sex, or ethnicity. In multivariate analyses, BMI (OR = 1.13 per kg/m 2 ; P = 0.012), family history (OR= 5.55; P = 0.014), and ALT (OR = 1.16; P= 0.012) were associated with DM. Conclusion: These findings suggest a complex interaction among genetic factors, body composition, and liver injury in the pathogenesis of DM in HIV-infected patients.

BACKGROUND Herpes zoster occurs at all CD4 cell counts in HIV-infected adults. It was hypothesized that even in the era of highly active antiretroviral therapy (HAART), zoster risk is higher in HIV-infected than uninfected women. METHODS Generalized estimating equations modeled self-reported occurrence of zoster between semiannual visits among 1832 HIV-infected and 489 HIV-uninfected women in the Women's Interagency HIV Study followed for up to 7.5 years. RESULTS A total of 337 (18.4%) HIV-infected and 7 (1.4%) HIV-uninfected women reported zoster at some time during follow-up. Using HIV-infected women with CD4 >750 cells/microL as the reference category, the odds ratios for reporting zoster since the prior visit were: 1.43 (95% CI 0.86-2.37) for CD4 500-749 cells/microL, 2.07 (95% CI 1.27-3.38) for CD4 350-499 cells/microL, 2.72 (95% CI 1.66-4.46) for CD4 200-349 cells/microL, and 3.16 (95% CI 1.92-5.18) for CD4

BACKGROUND Total lymphocyte count (TLC) and hemoglobin level have been suggested as useful and inexpensive parameters to indicate need for HAART in settings in which CD4 cell counts are unavailable. If delayed-type hypersensitivity (DTH) response predicts clinical response in persons using highly active antiretroviral therapy (HAART), it may also prove useful in resource-poor settings. OBJECTIVE To examine whether TLC, hemoglobin, and DTH response observed prior to initiation of HAART predict post-HAART clinical response. DESIGN Prospective cohort study. PARTICIPANTS 873 women in the Women's Interagency HIV Study. MEASUREMENTS TLC, hemoglobin, CD4 cell counts, and DTH testing using mumps, candida, and tetanus toxoid antigens, performed within 1 year prior to HAART initiation; death; self-report of initiation of HAART use and AIDS-defining illness (ADI). RESULTS Three different multivariate analyses were performed: 2 models that excluded CD4 cell count and assessed TLC at either < 850 or < 1250 cells/microL, and 1 model that excluded TLC and included CD4 < 200 cells/microL. TLC < 850, TLC < 1250, CD4 < 200 cells/microL, anergy to DTH testing, hemoglobin < 10.6 g/dL, and a pre-HAART report of ADI were each consistently independently associated both with death and with incident ADI. Log likelihood chi2 values suggested similar power among the 3 models in predicting both death and incident ADI. CONCLUSIONS Pre-HAART TLC, hemoglobin level, anergy to DTH testing, and clinical disease each independently predicted morbidity and death after HAART initiation. These findings support the use of TLC to guide decision-making for HAART initiation and suggest that further study of TLC, hemoglobin level, and DTH responses as an indication to provide HAART may be useful in resource-limited settings.

Objective: We investigated whether distress was independently associated with more rapid progression to AIDS among HIV-infected injection drug users (IDUs). Design: A cohort study of IDUs in Baltimore followed from 1988 through 1999. A total of 451 IDUs met the eligibility criteria of being HIV-seropositive but AIDS-free at baseline. Methods: We used Cox proportional hazards models to investigate progression to AIDS within 2 years of baseline, controlling for CD4 lymphocyte count, HIV-1 viral load, and oral thrush. Results: Of the 451 participants, 76.I%. were male and 95.8% were African-American; the median age at enrollment was 34 years. The cumulative incidence of AIDS within 2 years of baseline was 7. 1 %. In multiple regression analysis, distress was associated with more rapid time to AIDS (adjusted relative hazard [RH] = 2.39; 95% CI:1.16-4.90). The strongest association was observed among IDUs with the lowest (

Objectives: To determine incidence of HIV and associated risk factors in two cohorts of men working at a sugar estate in rural Malawi. Design: Prospective studies. Methods: After counseling and obtaining informed consent, male workers were tested for HIV-1 and syphilis. Baseline HIV-seronegative men were enrolled in two follow-up studies in 1994 and 1998, and were retested for HIV and syphilis at 6-month follow-up visits. Demographic, behavioral, and medical history was collected at baseline. Cumulative HIV incidence based on Kaplan-Meier methods was estimated. HIV incidence was also estimated per 100 person-years (p-y). Crude and adjusted rate ratios for the association of risk factors with incident HIV infection were obtained using Cox proportional hazards models. Results: HIV prevalence was 24.3% among 1692 men screened in 1994 and 21.0% among 1349 men screened in 1998 (p