Amanda A. Allshouse

Sex, Race, and Geographic Region Influence Clinical Outcomes Following Primary HIV-1 Infection

BACKGROUND It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection. METHODS Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters. RESULTS Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log₁₀ fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/μL (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience >1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, >1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001). CONCLUSIONS Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.

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.

Sex hormones in women with and without migraine: Evidence of migraine-specific hormone profiles

Objective: To compare daily sex hormone levels and rates of change between women with history of migraine and controls. Methods: History of migraine, daily headache diaries, and daily hormone data were collected in ovulatory cycles of pre- and early perimenopausal women in the Study of Womens Health Across the Nation. Peak hormone levels, average daily levels, and within-woman day-to-day rates of decline over the 5 days following each hormone peak were calculated in ovulatory cycles for conjugated urinary estrogens (E1c), pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone. Comparisons were made between migraineurs and controls using 2-sample t tests on the log scale with results reported as geometric means. Results: The sample included 114 women with history of migraine and 223 controls. Analyses of within-woman rates of decline showed that E1c decline over the 2 days following the luteal peak was greater in migraineurs for both absolute rate of decline (33.8 [95% confidence interval 28.0–40.8] pg/mgCr vs 23.1 [95% confidence interval 20.1–26.6] pg/mgCr, p = 0.002) and percent change (40% vs 30%, p < 0.001). There was no significant difference between migraineurs and controls in absolute peak or daily E1c, pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone levels. Secondary analyses demonstrated that, among migraineurs, the rate of E1c decline did not differ according to whether a headache occurred during the cycle studied. Conclusions: Migraineurs are characterized by faster late luteal phase E1c decline compared to controls. The timing and rate of estrogen withdrawal before menses may be a marker of neuroendocrine vulnerability in women with migraine.

Relative contributions of oligomenorrhea and hyperandrogenemia to the risk of metabolic syndrome in midlife women

CONTEXT Young reproductive-age women with irregular menses and androgen excess are at high risk for unfavorable metabolic profile; however, recent data suggest that menstrual regularity and hyperandrogenism improve with aging in affected women approaching menopause. OBJECTIVE The objective of the study was to determine whether women with hyperandrogenemia (HA) and a history of oligomenorrhea (Oligo) are at an elevated risk for metabolic syndrome (MetS) at the early stages of menopausal transition. METHODS Baseline data from 2543 participants (mean age of 45.8 yr) in the Study of Womens Health Across the Nation were analyzed. Women with a lifetime history of more than one 3-month interval of nongestational and nonlactational amenorrhea were classified as having a history of Oligo. The highest tertile of serum testosterone was used to define HA. Women with normal serum androgens and eumenorrhea were used as the reference group. Logistic regression models generated adjusted odds ratios (AOR), controlling for age, ethnicity, body mass index, smoking, and study site. RESULTS Oligo was associated with MetS only when coincident with HA [AOR of 1.93 for Oligo and HA [95% confidence interval (CI) 1.17-3.17], AOR of 1.25 for Oligo and normal androgens (95% CI 0.81-1.93)]. In contrast, HA conferred a consistently significant risk for MetS, regardless of the menstrual frequency status [AOR of 1.48 for HA and eumenorrhea (95% CI 1.15-1.90)]. CONCLUSIONS Our results suggest that HA but not history of Oligo is independently associated with the risk of prevalent MetS in pre- and perimenopausal women in their 40s.

Hyperandrogenic Oligomenorrhea and Metabolic Risks Across Menopausal Transition

CONTEXT Although there is evidence of metabolic risks in young women with irregular menses and androgen excess, persistence of risks after menopause is unclear. OBJECTIVE The objective of the study was to determine the impact of menopause on the cardiometabolic profile in women with high androgens and a history of menstrual irregularity. METHODS Study of Womens Health Across the Nation is a longitudinal cohort study. Data from 1929 women without metabolic syndrome (MetS) at baseline were analyzed for incidence of MetS, self-reported stroke, and myocardial infarction. Cox hazard ratios (HRs) were estimated, adjusting for age, ethnicity, body mass, smoking, menopausal status, and study site. RESULTS Among MetS-free women at baseline, 497 new cases were identified during 20 249 woman-years of follow-up over 12 years. Women with hyperandrogenemia (HA) and oligomenorrhea (Oligo) developed incident cases of MetS at a comparable rate compared with their counterparts: eumenorrheic, normoandrogenic women [HR 1.4 (0.9-2.2)], oligomenorrheic, normoandrogenic women [HR 1.3 (0.8-2.2)], and eumenorrheic hyperandrogenic women [HR 1.2 (0.7-1.8)]. Smoking and obesity were the strongest predictors of incident MetS. There was no significant difference in incidence of self-reported stroke or MI by HA/Oligo status. CONCLUSIONS Longitudinal evidence suggests that a history of androgen excess and menstrual irregularity is not associated with worsening of metabolic health after menopause. Our findings challenge the notion that a history of concurrent HA and Oligo reflects ongoing cardiometabolic risk in postmenopausal women.

Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

OBJECTIVE We sought to determine if maternal weight or body mass index (BMI) modifies the effectiveness of 17-alpha hydroxyprogesterone caproate (17OHP-C). STUDY DESIGN We performed a secondary analysis of the Maternal-Fetal Medicine Units Network Trial for the Prevention of Recurrent Preterm Delivery by 17-Alpha Hydroxyprogesterone Caproate. Binomial regression models were estimated to determine the relative risk (RR) of preterm birth (PTB) in women randomized to 17OHP-C vs placebo according to BMI category and maternal weight. Adjusted models considered inclusion of potential confounders. RESULTS In all, 443 women with complete data were included. 17OHP-C is effective in preventing PTB <37 weeks only in women with prepregnancy BMI <30 kg/m(2) (RR, 0.54; 95% confidence interval, 0.43-0.68). Above this BMI threshold there is a nonsignificant trend toward an increased risk of PTB (RR, 1.55; 95% confidence interval, 0.83-2.89) with 17OHP-C treatment. When analyzing by maternal weight, a similar threshold is observed at 165 lb, above which 17OHP-C is no longer effective. CONCLUSION The effectiveness of 17OHP-C is modified by maternal weight and BMI, and treatment does not appear to reduce the rate of PTB in women who are obese or have a weight >165 lb. This finding may be due to subtherapeutic serum levels in women with increased BMI or weight. Studies of adjusted-dose 17OHP-C in women who are obese or who weigh >165 lb are warranted, and current recommendations regarding the uniform use of 17OHP-C regardless of maternal BMI and weight may deserve reassessment.

Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study

Objective:Early initiation of low-dose aspirin (LDA) may reduce preeclampsia risk. We sought to determine whether LDA was beneficial when initiated <17w0d, within a trial of high-risk women enrolled <26w0d.Study Design:Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin study, including women enrolled <17w0d, randomized to LDA (60 mg day−1) or placebo with chronic hypertension (CHTN, n=186), diabetes (n=191) or prior preeclampsia (n=146). The primary outcome was preeclampsia at any time in pregnancy, secondary outcomes were early preeclampsia (<34w0d), late preeclampsia (⩾34w), small for gestational age (SGA; neonatal birthweight <10th %) and composite (early preeclampsia or SGA). Outcomes were compared by exact Χ2-tests.Results:Baseline characteristics were similar between treatment groups. Aspirin was associated with a lower rate of late-onset preeclampsia ⩾34w (17.36% vs 24.42%, P=0.047), with a 41% reduction in women with CHTN (18.28% vs 31.18%, P=0.041). There were no other significant differences in the outcome.Conclusion:Aspirin initiated <17w0d reduced the risk for late-onset preeclampsia by 29% supporting the practice of early initiation of aspirin in high-risk women.