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1.  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.
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
2.  Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study 
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.
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.
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.
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.
PMCID: PMC3904465  PMID: 24373482
HAART; Adherence; Herpes zoster; Incidence; Propensity score
3.  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).
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.
PMCID: PMC3440547  PMID: 22618868
race; ethnicity; viral hepatitis; mortality; gender
4.  Negative Predictive Value of Pap Testing: Implications for Screening Intervals for Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):791-797.
To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value.
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.
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).
Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate.
PMCID: PMC3448928  PMID: 22996096
5.  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.
PMCID: PMC3321069  PMID: 22120980
vaginal; HPV; hysterectomy; viral tropism; HIV
6.  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.
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).
A cross-sectional study.
WIHS, a multicenter prospective study.
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).
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.
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.
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.
PMCID: PMC3389125  PMID: 22494925
Vitamin D; anti-mullerian hormonem mullerian inhibiting substance; HIV; ovarian reserve; insulin resistance; obesity
8.  Effect of Human Immunodeficiency Virus Infection on the Prevalence and Incidence of Vaginal Intraepithelial Neoplasia 
Obstetrics and Gynecology  2012;119(3):582-589.
To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia in human immunodeficiency virus (HIV)-seropositive women.
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.
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.
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.
PMCID: PMC3285255  PMID: 22353957
9.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
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.
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.
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.
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.
PMCID: PMC3556987  PMID: 22820789
10.  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
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).
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.
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.
PMCID: PMC3267811  PMID: 22240540
Immune response; Vaccination; H1N1; Myelosuppression; Immunosuppression
11.  Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults 
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.
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.
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.
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.
Immunosuppression may contribute to increased persistence or progression of oral HPV infection.
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
12.  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.
To determine the incidence rate of, and the relative time to pregnancy by HIV status in US women between 2002 and 2009.
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.
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.
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.
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.
PMCID: PMC3496791  PMID: 21297418
women; HIV; pregnancy; time to pregnancy; parity
13.  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.
To describe the natural history of genital warts and vulvar intraepithelial neoplasia (VIN) in women with human immunodeficiency virus (HIV).
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.
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.
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.
PMCID: PMC3178036  PMID: 21934446
14.  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.
PMCID: PMC3442364  PMID: 21505313
15.  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.
PMCID: PMC3100515  PMID: 21606539
16.  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.
PMCID: PMC3079399  PMID: 21507924
17.  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.
PMCID: PMC3319124  PMID: 12599073
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.
PMCID: PMC3047594  PMID: 21075370
Ovarian reserve; chemotherapy; cancer; Mullerian inhibiting substance; Anti mullerian hormone; brain-derived neurotrophic factor
19.  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.
PMCID: PMC3187522  PMID: 21849458
20.  Presumed Cases of Mumps in Pregnancy: Clinical and Infection Control Implications 
Recently, a mumps outbreak in New York and New Jersey was reported by the Centers for Disease Control and Prevention (CDC). Subsequently, the dissemination of the disease was rapid, and, from June 28th 2009 through January 29th 2010, a total of 1,521 cases of mumps were reported in New York and New Jersey. Seven presumed cases occurred in pregnant women cared for at our institution. Mumps diagnosis as per the NYC Department of Health and Mental Hygiene was based on clinical manifestations, particularly parotitis. Prior immunizations with mumps vaccine and negative IgM were not adequate to rule out mumps infections. All of our seven patients had exposure to mumps in either their household or their community, and some of the them had symptoms of mumps. Due to the difficulties in interpreting serologies of these patients, their cases led to a presumed diagnosis of mumps. The diagnosis of mumps lead to the isolation of patients and health care personnel that were in contact with them. In this paper, we detail the presenting findings, diagnostic dilemmas and infection control challenges associated with presumed cases of mumps in pregnancy.
PMCID: PMC3296145  PMID: 22505798
21.  Impact of stress and depression on the frequency of squamous intraepithelial lesions 
To explore previously reported associations between cervical squamous lesions and psychological measures of stress and depression.
In a multicenter cohort study, HIV infected and seronegative comparison women had Pap tests and completed self-report questionnaires including the Perceived Stress Scale-10 (PSS), which measures perceived stress; the PTSD Civilian Symptom Checklist (PCL-C), which measures symptoms of posttraumatic stress disorder; and the Center for Epidemiologic Studies Depression Scale (CES-D), which measures depressive symptoms.
Median scores were 13 (range 0–38) for the PSS, 24 (range 17–85) for the PCL-C, and 8 (range 0–57), for the CES-D, indicating moderate stress and minimal depression. For PSS, compared to women in the lowest tertile of reported stress, O.R. for SIL was 0.88 (95% C.I. 0.50–1.54) for women in the middle tertile and 0.96 (95% C.I. 0.54–1.68) for women in the highest tertile. For PCL-C, compared to women in the lowest tertile of PTSD symptoms, O.R. for SIL was 0.79 (95% C.I. 0.43–1.41) for women in the middle tertile and 1.17 (95% C.I. 0.68–2.01) for women in the highest tertile. SIL rates were similar for CES-D scores ≥16 (compared to women with lower scores O.R. 1.41, 95% C.I. 0.88–2.26) and ≥ 23 (O.R. 1.39, 95% C.I. 0.81–2.40). In multivariable analysis including number of sexual partners, age, income, ethnicity, and serostatus, stress as measured by PSS and PCL-C, and depressive symptoms as measured by CES-D remained unassociated with SIL.
We found no evidence that stress and depression affect the prevalence of cervical squamous lesions.
PMCID: PMC3084664  PMID: 21192176
stress; depression; cervical lesion; Papanicolaou test
22.  CCR2 Genotype and Disease Progression in a Treated Population of HIV Type 1–Infected Women 
Both antiretroviral therapy and the human coreceptor polymorphism CCR2-V64I slow progression of human immunodeficiency virus type 1 (HIV-1) disease. To examine the effect of V64I on disease progression in patients receiving therapy, we determined CCR2 genotypes in the Women’s Interagency HIV Study cohort. We studied 2047 HIV-1–infected women, most of whom initiated treatment during the study. No association was seen between CCR2 genotype and either disease progression or therapeutic response, suggesting that the benefits of treatment most likely overshadow the salutary effects of the V64I polymorphism.
PMCID: PMC3164116  PMID: 15472820
23.  Associations of Insulin-Like Growth Factor (IGF)–I and IGF-Binding Protein–3 with HIV Disease Progression in Women 
The Journal of infectious diseases  2008;197(2):319-327.
The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)–3 has an opposing effect, inhibiting hematopoietic stem cell development.
We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]).
Low IGF-I levels (Ptrend = .02) and high IGFBP-3 levels (Ptrend = .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30–5.42]; Ptrend = .02) in multivariable models.
These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.
PMCID: PMC3127259  PMID: 18177247
24.  Cervical Shedding of HIV-1 RNA Among Women With Low Levels of Viremia While Receiving Highly Active Antiretroviral Therapy 
Among women with low o r undetectable quantities of HIV-1 RNA in plasma, factors associated with genital HIV-1 RNA shedding, including choice of treatment regimen, are poorly characterized.
We measured HIV-1 RNA in cervical swab specimens obtained from participants in the Women’s Interagency HIV Study who had concurrent plasma viral RNA levels <500 copies/mL, and we assessed factors associated with genital HIV shedding. The study was powered to determine the relative effects of antiretroviral protease inhibitors (PIs) versus nonnucleoside reverse transcriptase inhibitors (NNRTIs) on viral RNA shedding.
Overall, 44 (15%) of 290 women had detectable HIV-1 RNA in cervical specimens. In the final multivariate model, shedding was independently associated with NNRTI (vs. PI) use (odds ratio [OR], 95% confidence interval [CI]: 2.24, 1.13 to 4.45) and illicit drug use (OR, 95% CI: 2.41, 0.96 to 5.69).
This is the largest study to define risks for genital HIV-1 RNA shedding in women with low/undetectable plasma virus. Shedding in this population was common, and NNRTI-based highly active antiretroviral therapy (HAART) (vs. PI-based HAART) was associated with genital HIV shedding. Further study is required to determine the impact of these findings on transmission of HIV from mother to child or to sexual partners.
PMCID: PMC3126662  PMID: 17106279
compartmentalization; genital; HIV; nonnucleoside reverse transcriptase inhibitor; protease inhibitor; undetectable; viral replication; women
25.  Causes of Death among Women with Human Immunodeficiency Virus Infection in the Era of Combination Antiretroviral Therapy 
The American journal of medicine  2002;113(2):91-98.
To examine changes in the causes of death and mortality in women with human immunodeficiency virus (HIV) infection in the era of combination antiretroviral therapy.
Among women with, or at risk of, HIV infection, who were enrolled in a national study from 1994 to 1995, we used an algorithm that classified cause of death as due to acquired immunodeficiency syndrome (AIDS) or non-AIDS causes based on data from death certificates and the CD4 count. Poisson regression models were used to estimate death rates and to determine the risk factors for AIDS and non-AIDS deaths.
Of 2059 HIV-infected women and 569 who were at risk of HIV infection, 468 (18%) had died by April 2000 (451 HIV-infected and 17 not infected). Causes of death were available for 428 participants (414 HIV-infected and 14 not infected). Among HIV-infected women, deaths were classified as AIDS (n = 294), non-AIDS (n = 91), or indeterminate (n = 29). The non-AIDS causes included liver failure (n = 19), drug overdose (n = 16), non-AIDS malignancies (n = 12), cardiac disease (n = 10), and murder, suicide, or accident (n = 10). All-cause mortality declined an average of 26% per year (P = 0.03) and AIDS-related mortality declined by 39% per year (P = 0.01), whereas non-AIDS-related mortality remained stable (10% average annual decrease, P = 0.73). Factors that were independently associated with non-AIDS-related mortality included depression, history of injection drug use with hepatitis C infection, cigarette smoking, and age.
A substantial minority (20%) of deaths among women with HIV was due to causes other than AIDS. Our data suggest that to decrease mortality further among HIV-infected women, attention must be paid to treatable conditions, such as hepatitis C, depression, and drug and tobacco use.
PMCID: PMC3126666  PMID: 12133746

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