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1.  Common Clinical Conditions – Age, Low BMI, Ritonavir Use, Mild Renal Impairment - Affect Tenofovir Pharmacokinetics in a Large Cohort of HIV-Infected Women 
AIDS (London, England)  2014;28(1):59-66.
Objective
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
Design
Intensive pharmacokinetic (PK) studies of tenofovir in a large, diverse cohort of HIV-infected women over 24-hours at steady-state were performed and factors that influenced exposure (assessed by areas-under-the-time-concentration curves, AUCs) identified
Methods
HIV-infected women (n=101) on tenofovir-based therapy underwent intensive 24-hour PK sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight and body mass index (BMI) were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFR) prior to starting tenofovir were estimated by the CKD-EPI equation using both creatinine and cystatin-C measures
Results
The median (range) of tenofovir AUCs was 3350 (1031–13,911) ng x h/mL. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, p 0.002), increasing age (1.21-fold increase per decade, p=0.0007) and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70mL/min, p=0.0075).
Conclusions
Concomitant ritonavir use, increasing age, decreasing BMI and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
doi:10.1097/QAD.0000000000000033
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C
2.  Abnormal Pap tests and human papillomavirus infections among HIV infected and uninfected women who have sex with women 
Objective
To estimate the frequency of abnormal Pap and human papillomavirus (HPV) positivity among HIV seropositive and seronegative women who have sex with women (WSW).
Methods
Pap and HPV DNA PCR tests were obtained every six months from women in a U.S. cohort of HIV seropositive and seronegative women. WSW were women reporting no male and at least one female sex partner over five years. WSW were frequency matched 1:5 to women reporting sex only with men (WSM) and assessed using multivariable generalized estimating equation logistic regression models.
Results
Paps at study entry were abnormal in 12 (21%) of 49 HIV seropositive WSW, 151 (64%) of 245 HIV seropositive WSM, 3 (9%) of 24 HIV seronegative WSW, and 16 (11%) of 120 seronegative WSM. HPV was found at entry in 18 (42%) HIV seropositive WSW, 109 (52%) HIV seropositive WSM, 6 (27%) HIV seronegative WSW and 13 (13%) HIV seronegative WSM. After controlling for HIV serostatus and CD4 count, WSW had marginally lower odds than WSM of Pap abnormality (O.R. 0.59, 95% C.I. 0.33, 1.03) and of HPV (O.R. 0.53, 95% C.I. 0.32, 0.89). After controlling for partner gender, HIV seropositivity and lower CD4 count were associated with any HPV, oncogenic HPV, any abnormal Pap result, and HSIL or worse (P < 0.0001 for all).
Conclusion
While risks for abnormal Pap and HPV are modestly lower in WSW than WSM, both are common in HIV seropositive women regardless of sexual preference. WSW and WSM should be screened similarly.
doi:10.1097/LGT.0b013e3182942733
PMCID: PMC3905442  PMID: 23959300
Human papillomavirus; HIV in women; women who have sex with women
3.  Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study 
Journal of neurovirology  2013;19(6):574-585.
Objective
To explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection.
Design/Methods
1690 participants (1196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity.
Results
Among HIV+ women, BMI < 18.5 kg/m2 was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m2 or higher) was related to better performance on Trails B and worse performance on the Stroop Interference test. Among HIV- women, an obese BMI was related to worse performance on the Stroop – Color naming test. Few and inconsistent associations were observed between WC, WHR and cognition.
Conclusion
Among women at mid-life with chronic (at least 10 years) HIV infection, common anthropometric measures, primarily BMI, were differentially related to cognitive test performance by cognitive domain. Higher levels of BMI were associated with better cognitive function. In this era of antiretroviral therapies, restoration of health evidenced as higher BMI due to effective antiretroviral therapies, may improve cognitive function in middle-aged HIV infected women.
doi:10.1007/s13365-013-0219-1
PMCID: PMC3957488  PMID: 24338243
Cognition; HIV; Women; Overweight; Obesity; Middle-Aged
4.  MEAN PLATELET VOLUME IS DECREASED IN HIV INFECTED WOMEN 
HIV medicine  2013;14(9):549-555.
Objectives
HIV infection is associated with higher than expected cardiovascular event rates and lowered platelet counts. These conditions are associated with an elevation of mean platelet volume (MPV). The present study compares MPV in HIV-infected and uninfected women and identifies factors influencing MPV values in HIV-infected women.
Methods
A total of 234 HIV-infected and 134 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had MPV values obtained. HIV-infected women were older, more likely to have diabetes, and have higher triglyceride levels than HIV-uninfected women.
Results
The mean platelet count was lower in HIV infected vs. uninfected women (249/µl 95% CI 238, 259 vs. 276/µl 95% CI 265, 287, p<0.01). Adjusted mean MPV values were lower in the HIV- infected than in the uninfected group (8.66 fl 95% CI 8.52, 8.79 vs. 9.05 fl 95% CI 8.87, 9.24). In multiple regression analysis after adjusting for other covariates, MPV was positively associated with platelet count, and negatively with HIV infection (model R2=0.20 p<0.01). In multiple regression analysis confined to HIV-infected women, a lower MPV was independently associated with history of AIDS defining illness (R2=0.28 p=0.03), but not with CD4 nadir count or HAART use.
Conclusions
HIV-infected women have lower MPV values than-uninfected women suggesting impaired production rather than increased destruction. Higher than expected cardiovascular event rates, cannot be attributed to greater platelet reactivity as measured by MPV.
doi:10.1111/hiv.12048
PMCID: PMC3775876  PMID: 23738819
HIV; mean platelet volume; WIHS
5.  Plasma and Mucosal HIV Viral Loads Are Associated with Genital Tract Inflammation In HIV-Infected Women 
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 (WIHS) to explore the hypothesis that compared to 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
19 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). CVL antimicrobial activity was also determined.
Results
Compared to HIV-uninfected, HIV+-HVL women had higher levels of mucosal, but not systemic pro-inflammatory cytokines and chemokines, higher Nugent scores, and lower E. 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 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.
Conclusion
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.
doi:10.1097/QAI.0b013e3182961cfc
PMCID: PMC3706034  PMID: 23591635
HIV; HSV; mucosal immunity; inflammation; female genital tract; WIHS
6.  Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women 
AIDS (London, England)  2013;27(11):1743-1751.
Objective
To assess factors associated with concomitant anal and cervical human papillomavirus (HPV) infections in HIV-infected and at-risk women.
Design
A study nested within the Women’s Interagency HIV Study (WIHS), a multi-center longitudinal study of HIV-1 infection in women conducted in six centers within the United States.
Methods
Four hundred and seventy HIV-infected and 185 HIV-uninfected WIHS participants were interviewed and examined with anal and cervical cytology testing. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV testing. Women with abnormal cytologic results had colposcopy or anoscopy-guided biopsy of visible lesions. Logistic regression analyses were performed and odds ratios (ORs) measured the association for concomitant anal and cervical HPV infection.
Results
One hundred and sixty-three (42%) HIV-infected women had detectable anal and cervical HPV infection compared with 12 (8%) of the HIV-uninfected women (P <0.001). HIV-infected women were more likely to have the same human papillomavirus (HPV) genotype in the anus and cervix than HIV-uninfected women (18 vs. 3%, P <0.001). This was true for both oncogenic (9 vs. 2%, P = 0.003) and nononcogenic (12 vs. 1%, P <0.001) HPV types. In multivariable analysis, the strongest factor associated with both oncogenic and nononcogenic concomitant HPV infection was being HIV-infected (OR = 4.6 and OR = 16.9, respectively). In multivariable analysis of HIV-infected women, CD4+ cell count of less than 200 was the strongest factor associated with concomitant oncogenic (OR = 4.2) and nononcogenic (OR = 16.5) HPV infection.
Conclusion
HIV-infected women, particularly those women with low CD4+ cell counts, may be good candidates for HPV screening and monitoring for both cervical and anal disease
doi:10.1097/QAD.0b013e3283601b09
PMCID: PMC3917497  PMID: 23803793
anal intraepithelial neoplasia; cervical intraepithelial neoplasia; HIV-infection; human papillomavirus; women
7.  Relation of HLA Class I and II Supertypes with Spontaneous Clearance of Hepatitis C Virus 
Genes and immunity  2013;14(5):330-335.
Human leukocyte antigen (HLA) genotype has been associated with probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; p=0.004) was associated with HCV persistence while DR8 (PR=1.8; p=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became non-significant in analysis that included supertypes while B*57:03 (PR=1.9; p=0.008) and DRB1*07:01 (PR=1.7; p=0.005) retained significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.
doi:10.1038/gene.2013.25
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
8.  Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study 
Background
Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied.
Methods
The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women’s Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence.
Results
Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load.
Conclusions
Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.
doi:10.1186/1742-6405-10-34
PMCID: PMC3904465  PMID: 24373482
HAART; Adherence; Herpes zoster; Incidence; Propensity score
9.  Lower Liver-Related Death in African American Women With HIV/HCV Co-Infection Compared to Caucasian and Hispanic Women 
Hepatology (Baltimore, Md.)  2012;56(5):1699-1705.
Among individuals with and without concurrent human immunodeficiency virus (HIV), racial/ethnic differences in the natural history of hepatitis C virus (HCV) have been described. African-Americans have lower spontaneous HCV clearance than Caucasians, yet slower rates of liver fibrosis once chronically infected. It is not clear how these differences in the natural history of hepatitis C affect mortality, in either HIV positive or negative individuals. We conducted a cohort study of HIV/HCV co-infected women followed in the multicenter, NIH-funded Women’s Interagency HIV Study (WIHS) to determine the association of self-reported race/ethnicity with all-cause and liver-related mortality. Survival analyses were performed using Cox proportional hazards models. The eligible cohort (n=794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. There were 438 deaths and 49 liver-related deaths during a median follow-up of 8.9 years and maximum follow-up of 16 years. African American co-infected women had significantly lower liver-related mortality compared to Caucasian (HR 0.41 95% CI 0.19–0.88, p=0.022) and Hispanic co-infected women (HR 0.38 95% CI 0.19–0.76, p=0.006). All-cause mortality was similar between racial/ethnic groups (HRs for all comparisons 0.82–1.03, logrank p=0.8).
Conclusions
African American co-infected women were much less likely to die from liver disease as compared to Caucasians and Hispanics, independent of other causes of death. Future studies are needed to investigate the reasons for this marked racial/ethnic discrepancy in liver-related mortality.
doi:10.1002/hep.25859
PMCID: PMC3440547  PMID: 22618868
race; ethnicity; viral hepatitis; mortality; gender
10.  Negative Predictive Value of Pap Testing: Implications for Screening Intervals for Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):791-797.
Objective
To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value.
Methods
Participants in the Women’s Interagency HIV Study were followed with conventional Pap smears every 6 months. After excluding those with abnormal Pap tests before study, cervical disease, or hysterectomy, women with negative enrollment Pap results were followed for development within 15 or within 39 months of precancer, defined as a Pap read as high grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2+. Correlations between one or more consecutive negative Pap results and subsequent precancer were assessed using Cox proportional hazards models.
Results
Among 942 HIV infected women with negative baseline Pap tests, 8 (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap tests, precancer was rare, with no cases within 15 months and 10/539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap tests. Risks for precancer within 15 months after negative Pap included current smoking (aHR 1.5, 95% CI 1.2, 2.0 vs nonsmokers), younger age (aHR=1.5, 95% CI 1.1, 2.1 for women aged younger than 31 years vs older than 45 years) and lower CD4 count (aHR 11.8, 95% CI 1.3, 2.3 for CD4 200–500, aHR 2.2, 95% CI 1.6, 2.9 for CD4 <200/cmm, vs CD4 >500/cmm).
Conclusion
Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate.
doi:10.1097/AOG.0b013e31826a8bbd
PMCID: PMC3448928  PMID: 22996096
11.  Cervicovaginal HPV Infection Before and After Hysterectomy: Evidence of Different Tissue Tropism for Oncogenic and Non-Oncogenic HPV Types in a Cohort of HIV-positive and HIV-negative Women 
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of non-oncogenic HPV types in the vagina. In the current investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by PCR. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group – before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% versus 12%; P<0.001) and after hysterectomy (56% versus 6%; P<0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence (odds ratio [OR]=0.71; 95% confidence interval [CI]=0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR=0.48; 95%CI=0.35-0.66) than non-oncogenic HPV types (OR=0.89; 95%CI=0.71-1.11; Pinteraction=0.002). Overall, we observed greater reductions in oncogenic than non-oncogenic HPV prevalence following hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared with vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.
doi:10.1002/ijc.27363
PMCID: PMC3321069  PMID: 22120980
vaginal; HPV; hysterectomy; viral tropism; HIV
12.  Circulating Vitamin D Correlates with Serum Anti-Mullerian Hormone Levels in Late Reproductive-Aged Women: Women’s Interagency HIV Study 
Fertility and Sterility  2012;98(1):228-234.
Objective
To study the correlation between circulating 25 hydroxy-vitamin D (25OH-D) levels and serum AMH in women enrolled in the Women’s Interagency HIV Study (WIHS).
Design
A cross-sectional study.
Setting
WIHS, a multicenter prospective study.
Patient(s)
All premenopausal women (n=388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 (N=128), group 2 with age 35 to 39 (N=119), and group 3 with age ≥ 40 (N=141).
Intervention(s)
Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels.
Main Outcome Measure(s)
Correlation between 25OH-D and AMH before and after adjusting for HIV status, BMI, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate and geographic site of participation.
Result(s)
After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log10AMH for 25-year-olds (youngest participant) was −0.001 (SE=0.008, p=0.847); and for 45-year-olds (oldest participant), the corresponding slope was +0.011 (SE=0.005, p=0.021). Fasting insulin level was negatively correlated with serum AMH (p=0.016). The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE=0.006, p=0.764); in group 2 was +0.006 (SE=0.005, p=0.269); and in group 3 was +0.011 (SE=0.005, p=0.022). There was no association between HIV and AMH.
Conclusion(s)
A novel relationship is reported between circulating 25OH-D and AMH in women aged = 40 suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late reproductive-aged women.
doi:10.1016/j.fertnstert.2012.03.029
PMCID: PMC3389125  PMID: 22494925
Vitamin D; anti-mullerian hormonem mullerian inhibiting substance; HIV; ovarian reserve; insulin resistance; obesity
14.  Effect of Human Immunodeficiency Virus Infection on the Prevalence and Incidence of Vaginal Intraepithelial Neoplasia 
Obstetrics and Gynecology  2012;119(3):582-589.
Objective
To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia in human immunodeficiency virus (HIV)-seropositive women.
Methods
Pap tests were done semiannually for 335 HIV-seropositive and 75 HIV-seronegative women with prior hysterectomy in the prospective Women’s Interagency HIV Study cohort. Endpoints included abnormal Pap tests after hysterectomy and vaginal intraepithelial neoplasia regardless of hysterectomy.
Results
Over a median of 5.6 years of follow-up, vaginal Pap tests were abnormal at 1,076 (29%, 95% C.I. 25%, 33%) of 3,700 visits among HIV seropositive vs. 31 (4%, 95% C.I. 2%, 8%) of 763 visits among seronegative women (P < 0.001). Abnormal Pap tests included 641 atypical squamous cells of undetermined significance (ASC-US), 425 low-grade squamous intraepithelial lesions (LSIL), and 10 high-grade squamous intraepithelial lesions in HIV-seropositive women, and 28 ASC-US and three LSIL in HIV-seronegative women. The incidence of abnormal Pap tests after hysterectomy was 14/100 person-years among HIV-seropositive and 2/100 person-years among HIV-seronegative women (P < 0.001) and remained stable across time. The 5-year clearance rate of abnormal Pap tests was 34/100 person-years for HIV-seropositive and 116/100 person-years for HIV-seronegative women (P < 0.001). In multivariate regression models, women with lower CD4 counts were more likely to have and less likely to clear abnormal cytology when it occurred. The incidence of vaginal intraepithelial neoplasia 2+ was 0.2 and 0.01 per 100 person-years for HIV-seropositive and HIV-seronegative women (P = 0.001). Two HIV-seropositive women developed Stage II cancers, with remission after radiotherapy.
Conclusion
Vaginal Pap tests are often abnormal in HIV-seropositive women. Though more common than in HIV-seronegative women, vaginal intraepithelial neoplasia 2+ and especially vaginal cancers are infrequent.
doi:10.1097/AOG.0b013e318244ee3d
PMCID: PMC3285255  PMID: 22353957
15.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
Context
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
Objective
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
Results
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
Conclusion
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
doi:10.1001/jama.2012.5664
PMCID: PMC3556987  PMID: 22820789
16.  Immunogenicity of an Inactivated Monovalent 2009 Influenza A (H1N1) Vaccine in Patients Who Have Cancer 
The Oncologist  2012;17(1):125-134.
The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine. Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.
Learning Objectives
After completing this course, the reader will be able to: Cite the primary concerns of oncologists regarding influenza vaccination for their cancer patients.Describe research showing that cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine.
Patients and Methods.
We conducted a prospective single site study comparing the immune response after H1N1 vaccination of healthy controls (group A), patients who had solid tumors and were taking myelosuppressive chemotherapy (group B), patients who had solid tumors and were taking nonmyelosuppressive or no treatment (group C), and patients who had hematologic malignancies (group D).
Results.
At 2–6 weeks after vaccination, seroconversion was observed in 80.0% of group A (95% confidence interval [CI], 65.0%–89.7%), 72.2% of group B (95% CI, 55.9%–84.3%), 87.0% of group C (95% CI, 72.2%–94.7%), and 75.0% of group D (95% CI, 52.8%–89.2%) (p = NS). The geometric mean titer ratio, that is, geometric mean factor increase in antibody titer after vaccination, was 12.6 (95% CI, 7.9–19.9), 12.7 (95% CI, 7.3–22.1), 23.0 (95% CI, 13.9–38.2), and 12.1 (95% CI, 5.3–27.9) (p = NS), and the seroprotection rates were 95.5% (95% CI, 84.0%–99.6%), 79.0% (95% CI, 63.4%–89.2%), 90.5% (95% CI, 77.4%–96.8%), and 90.0% (95% CI, 71%–98.7%) in the corresponding groups (p = NS). Immune responses were robust regardless of malignancy, or time intervals between the use of myelosuppressive or immunosuppressive medications and vaccination. No participants developed clinical H1N1 infection.
Conclusion.
Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.
doi:10.1634/theoncologist.2011-0220
PMCID: PMC3267811  PMID: 22240540
Immune response; Vaccination; H1N1; Myelosuppression; Immunosuppression
17.  Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults 
Introduction
Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.
Methods
This study was nested within the MACS (men) and WIHS (women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope™ mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations (GEE) in this cross-sectional analysis.
Results
Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared to HIV-negative individuals (aOR=2.1, 95%CI=1.6–2.8). Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each p-trend<0.01). In contrast, among HIV-positive individuals lower CD4 T-cell count (p-trend<0.001) and higher number of lifetime sexual partners (p-trend=0.03) were strong risk factors.
Conclusions
Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV.
Impact
Immunosuppression may contribute to increased persistence or progression of oral HPV infection.
doi:10.1158/1055-9965.EPI-11-0734
PMCID: PMC3280125  PMID: 22045700
Oral HPV; HIV; risk factors; Head and Neck/Oral Cancer; Epidemiology; Infections and the etiology of cancer, Diet, Alcohol, Smoking, and other Lifestyle Factors; Biomarkers of Human Exposure to carcinogens and DNA damaging agents; DNA tumor viruses
18.  Relative time to pregnancy among HIV-infected and uninfected women in the Women’s Interagency HIV Study, 2002–2009 
AIDS (London, England)  2011;25(5):707-711.
Objectives
To determine the incidence rate of, and the relative time to pregnancy by HIV status in US women between 2002 and 2009.
Design
The Women’s Interagency HIV Study (WIHS) is an ongoing, multicenter prospective cohort study of the natural and treated history of HIV infection and related outcomes among women with and without HIV.
Methods
Eligible participants were ≤45 years of age; sexually active with male partner(s) or reported a pregnancy outcome within the past year; and never reported hysterectomy, tubal ligation, or oopherectomy. Poisson regression was conducted to compare pregnancy incidence rates over time by HIV status. Relative time to pregnancy was ascertained via Kaplan-Meier plots and generalized gamma survival analysis.
Results
Adjusting for age, number of male sex partners, contraception, parity, exchanging sex, and alcohol use, HIV infection was associated with a 40% reduction in the incidence rate of pregnancy (incidence rate ratio=0.60, 95% confidence interval: [C.I.] 0.46–0.78). The time for HIV-infected women to become pregnant was 73% longer relative to HIV-uninfected women (relative time=1.73, 95% C.I.: 1.35–2.36). In addition to HIV infection, decreased parity and older age were independent predictors of lower pregnancy incidence.
Conclusions
Despite the beneficial effects of modern antiretroviral therapy on survival and prevention of maternal-to-child transmission, our findings suggest that pregnancy incidence remains lower among HIV-infected women. Whether this lower incidence is due to behavioral differences or reduced biologic fertility remains an area worthy of further study.
doi:10.1097/QAD.0b013e3283445811
PMCID: PMC3496791  PMID: 21297418
women; HIV; pregnancy; time to pregnancy; parity
19.  Genital Warts and Vulvar Intraepithelial Neoplasia: Natural History and Effects of Treatment and Human Immunodeficiency Virus Infection 
Obstetrics and gynecology  2011;118(4):831-839.
Objective
To describe the natural history of genital warts and vulvar intraepithelial neoplasia (VIN) in women with human immunodeficiency virus (HIV).
Methods
A cohort of 2,791 HIV infected and 953 uninfected women followed for up to 13 years had genital examinations at 6-month intervals, with biopsy for lesions suspicious for VIN.
Results
The prevalence of warts was 4.4% (5.3% for HIV seropositive women and 1.9% for seronegative women, P < 0.0001). The cumulative incidence of warts was 33% (95% C.I. 30, 36%) in HIV seropositive and 9% (95% C.I. 6, 12%) in seronegative women (P < 0.0001). In multivariable analysis, lower CD4 lymphocyte count, younger age, and current smoking were strongly associated with risk for incident warts. Among 501 HIV seropositive and 43 seronegative women, warts regressed in 410 (82%) seropositive and 41 (95%) seronegative women (P = 0.02), most in the first year after diagnosis. In multivariable analysis, regression was negatively associated with HIV status and lower CD4 count as well as older age. Incident VIN of any grade occurred more frequently among HIV seropositive than seronegative women: 0.42 (0.33 – 0.53) vs 0.07 (0.02 – 0.18)/100 person-years (P < 0.0001). VIN2+ was found in 58 women (55 with and 3 without HIV, P < 0.001). Two women with HIV developed stage IB squamous cell vulvar cancers.
Conclusion
While genital warts and VIN are more common among HIV seropositive than seronegative women, wart regression is common even in women with HIV, and cancers are infrequent.
doi:10.1097/AOG.0b013e31821a0f4d
PMCID: PMC3178036  PMID: 21934446
20.  Seroincidence of 2009 H1N1 infection in HIV-infected and HIV-uninfected women prior to vaccine availability 
AIDS (London, England)  2011;25(9):1229-1232.
The 2009 H1N1 pandemic was a unique opportunity to investigate differences in influenza infection using serology by HIV status. Using serial serum specimens collected from 1 April to 30 September 2009 and the prior 2 years from Women’s Interagency HIV study participants, there was no difference in serologic evidence of 2009 H1N1 infection among HIV-infected women with a CD4 cell count at least 350 cells/µl compared with HIV-uninfected women. Owing to evidence showing a greater risk of influenza-related complications, HIV-infected individuals should continue to be a priority group for vaccination.
doi:10.1097/QAD.0b013e3283471cf2
PMCID: PMC3442364  PMID: 21505313
21.  The Relation of HLA Genotype to Hepatitis C Viral Load and Markers of Liver Fibrosis in HIV-Infected and HIV-Uninfected Women 
The Journal of Infectious Diseases  2011;203(12):1807-1814.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
doi:10.1093/infdis/jir192
PMCID: PMC3100515  PMID: 21606539
22.  Atazanavir Concentration in Hair Is the Strongest Predictor of Outcomes on Antiretroviral Therapy 
In a longitudinal study of outcomes on atazanavir-based therapy in a large cohort of HIV-infected women, hair levels of atazanavir were the strongest independent predictor of virologic suppression. Hair antiretroviral concentrations may serve as a useful tool in HIV care.
Background. Adequate exposure to antiretrovirals is important to maintain durable responses, but methods to assess exposure (eg, querying adherence and single plasma drug level measurements) are limited. Hair concentrations of antiretrovirals can integrate adherence and pharmacokinetics into a single assay.
Methods. Small hair samples were collected from participants in the Women's Interagency HIV Study (WIHS), a large cohort of human immunodeficiency virus (HIV)-infected (and at-risk noninfected) women. From 2003 through 2008, we analyzed atazanavir hair concentrations longitudinally for women reporting receipt of atazanavir-based therapy. Multivariate random effects logistic regression models for repeated measures were used to estimate the association of hair drug levels with the primary outcome of virologic suppression (HIV RNA level, <80 copies/mL).
Results. 424 WIHS participants (51% African-American, 31% Hispanic) contributed 1443 person-visits to the analysis. After adjusting for age, race, treatment experience, pretreatment viral load, CD4 count and AIDS status, and self-reported adherence, hair levels were the strongest predictor of suppression. Categorized hair antiretroviral levels revealed a monotonic relationship to suppression; women with atazanavir levels in the highest quintile had odds ratios (ORs) of 59.8 (95% confidence ratio, 29.0–123.2) for virologic suppression. Hair atazanavir concentrations were even more strongly associated with resuppression of viral loads in subgroups in which there had been previous lapses in adherence (OR, 210.2 [95% CI, 46.0–961.1]), low hair levels (OR, 132.8 [95% CI, 26.5–666.0]), or detectable viremia (OR, 400.7 [95% CI, 52.3–3069.7]).
Conclusions. Antiretroviral hair levels surpassed any other predictor of virologic outcomes to HIV treatment in a large cohort. Low antiretroviral exposure in hair may trigger interventions prior to failure or herald virologic failure in settings where measurement of viral loads is unavailable. Monitoring hair antiretroviral concentrations may be useful for prolonging regimen durability.
doi:10.1093/cid/cir131
PMCID: PMC3079399  PMID: 21507924
23.  CC Chemokine Receptor 5 Genotype and Susceptibility to Transmission of Human Immunodeficiency Virus Type 1 in Women 
The Journal of Infectious Diseases  2003;187(4):569-575.
The human gene for CC chemokine receptor 5, a coreceptor for human immunodeficiency virus type 1 (HIV-1), affects susceptibility to infection. Most studies of predominantly male cohorts found that individuals carrying a homozygous deleted form of the gene, Δ32, were protected against transmission, but protection did not extend to Δ32 heterozygotes. The role played by this mutation in HIV-1 transmission to women was studied in 2605 participants in the Women's Interagency HIV Study. The Δ32 gene frequency was 0.026 for HIV-1–seropositive women and 0.040 for HIV-1–seronegative women, and statistical analyses showed that Δ32 heterozygotes were significantly less likely to be infected (odds ratio, 0.63 [95% confidence interval, 0.44–0.90]). The CCR5 Δ32 heterozygous genotype may confer partial protection against HIV-1 infection in women. Because Δ32 is rare in Africans and Asians, it seems plausible that differential genetic susceptibility, in addition to social and behavioral factors, may contribute to the rapid heterosexual spread of HIV-1 in Africa and Asia.
doi:10.1086/367995
PMCID: PMC3319124  PMID: 12599073
24.  CHANGES IN PLASMA MULLERIAN INHIBITING SUBSTANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR AFTER CHEMOTHERAPY IN PREMENOPAUSAL WOMEN 
Fertility and sterility  2011;95(5):1790-1793.
Eight premenopausal women with cancer had blood drawn for brain-derived neurotrophic factor (BDNF) and Mullerian Inhibiting Substance (MIS) before and three months after receiving chemotherapy. Unlike MIS, BDNF levels were not reduced following chemotherapy.
doi:10.1016/j.fertnstert.2010.10.033
PMCID: PMC3047594  PMID: 21075370
Ovarian reserve; chemotherapy; cancer; Mullerian inhibiting substance; Anti mullerian hormone; brain-derived neurotrophic factor
25.  Human Leukocyte Antigen Genotype and Risk of HIV Disease Progression before and after Initiation of Antiretroviral Therapy▿‡ 
Journal of Virology  2011;85(20):10826-10833.
While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (β = −0.7; 95% confidence interval [CI] = −0.9 to −0.5; P = 5 × 10−11) and Bw4 (β = −0.2; 95% CI = −0.4 to −0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients.
doi:10.1128/JVI.00804-11
PMCID: PMC3187522  PMID: 21849458

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