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1.  Gender-related risk factors improve mortality predictive ability of VACS Index among HIV-infected women 
Adding gender-related modifiable characteristics or behaviors to the Veterans Aging Cohort Study (VACS) Index might improve the accuracy of predicting mortality among HIV-infected women on treatment. We evaluated the VACS Index in women with HIV, determined whether additional variables would improve mortality prediction, and quantified the potential for improved survival associated with reduction in these additional risk factors.
The VACS Index (based on age, CD4 count, HIV-1 RNA, hemoglobin, AST, ALT, platelets, creatinine and Hepatitis C status) was validated in HIV-infected women in the Women’s Interagency HIV Study (WIHS) who initiated antiretroviral therapy (ART) between January 1996 and December 2007. Models were constructed adding race, depression, abuse, smoking, substance use, transactional sex, and comorbidities to determine whether predictability improved. Population attributable fractions were calculated.
The VACS Index accurately predicted 5-year mortality in 1057 WIHS women with 1 year on HAART with c-index 0.83 (95% CI 0.79–0.87). In multivariate analysis, the VACS Index score (adjusted hazard ratio [aHR] for 5-point increment 1.30; 95% CI 1.25–1.35), depressive symptoms (aHR 1.73; 95% CI 1.17–2.56) and history of transactional sex (aHR 1.93; 95% CI 1.33–1.82) were independent statistically significant predictors of mortality.
Including depression and transactional sex significantly improved the performance of the VACS Index in predicting mortality among HIV-infected women. Providing treatment for depression and addressing economic and psychosocial instability in HIV infected women would improve health and perhaps point to a broader public health approach to reducing HIV mortality.
PMCID: PMC4644433  PMID: 26284531
HIV; Women; Mortality; Depression; Transactional Sex
2.  Cervical Precancer Risk in HIV-Infected Women Who Test Positive for Oncogenic Human Papillomavirus Despite a Normal Pap Test 
Human immunodeficiency virus-infected women with a normal Pap result who nonetheless test positive for human papillomavirus (HPV) type 16 have a high risk of cervical precancer that may warrant immediate colposcopy, whereas those positive for other oncogenic HPV types are at moderate risk.
Background. Determining cervical precancer risk among human immunodeficiency virus (HIV)–infected women who despite a normal Pap test are positive for oncogenic human papillomavirus (oncHPV) types is important for setting screening practices.
Methods. A total of 2791 HIV-infected and 975 HIV-uninfected women in the Women's Interagency HIV Study were followed semiannually with Pap tests and colposcopy. Cumulative risks of cervical intraepithelial neoplasia grade 2 or greater (CIN-2+; threshold used for CIN treatment) and grade 3 or greater (CIN-3+; threshold to set screening practices) were measured in HIV-infected and HIV-uninfected women with normal Pap tests, stratified by baseline HPV results, and also in HIV-infected women with a low-grade squamous intraepithelial lesion (LSIL; benchmark indication for colposcopy).
Results. At baseline, 1021 HIV-infected and 518 HIV-uninfected women had normal Pap tests, of whom 154 (15%) and 27 (5%), respectively, tested oncHPV positive. The 5-year CIN-2+ cumulative risk in the HIV-infected oncHPV-positive women was 22% (95% confidence interval [CI], 9%–34%), 12% (95% CI, 0%–22%), and 14% (95% CI, 2%–25%) among those with CD4 counts <350, 350–499, and ≥500 cells/µL, respectively, whereas it was 10% (95% CI, 0%–21%) in those without HIV. For CIN-3+, the cumulative risk averaged 4% (95% CI, 1%–8%) in HIV-infected oncHPV-positive women, and 10% (95% CI, 0%–23%) among those positive for HPV type 16. In HIV-infected women with LSIL, CIN-3+ risk was 7% (95% CI, 3%–11%). In multivariate analysis, HIV-infected HPV16-positive women had 13-fold (P = .001) greater CIN-3+ risk than oncHPV-negative women (referent), and HIV-infected women with LSIL had 9-fold (P < .0001) greater risk.
Conclusions. HIV-infected women with a normal Pap result who test HPV16 positive have high precancer risk (similar to those with LSIL), possibly warranting immediate colposcopy. Repeat screening in 1 year may be appropriate if non-16 oncHPV is detected.
PMCID: PMC4614409  PMID: 26187020
HIV; human papillomavirus; cervical cancer screening; Pap test
3.  Dysregulated B-cell TLR2 expression and Elevated Regulatory B cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma 
AIDS (London, England)  2015;29(13):1659-1664.
In Antiretroviral therapy (ART)-treated subjects, to determine if AIDS-related Non-Hodgkin Lymphoma (AIDS-NHL) is preceded by: i) elevated frequency of potentially malignant abnormal activated/ Germinal center (GC)-like B cells, ii) elevated serum prevalence of B-cell stimulatory TLR-ligands resulting from HIV-infection associated microbial translocation, iii) dysregulated B-cell TLR expression/signaling and iv) perturbations in the frequency of immunoregulatory cells.
A case-control study nested with a cohort study of HIV-infected women.
Pre-diagnostic AIDS-NHL cases (n=14, collected 1-12 months pre diagnosis) and controls (n=42) from the Women’s Interagency HIV Study (WIHS) cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/GC-like (CD19+CD10+CD71+CD86+AID+) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed.
Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/GC-like CD19+CD10+CD71+CD86+AID+ B cells (p=0.0072), elevated serum prevalence of TLR2-ligand and significantly elevated B-cell TLR2 expression (p=0.0015), positively correlating with the frequency of activated/GC-like B cells (rho=0.7273, p=0.0144). In cases, a purified subset of activated/GC-like B cells exhibited decreased expression of micro-RNAs that modulate TLR2-signaling, including: miR-21, 146a, 146b and 155. Finally, cases also exhibited significantly elevated frequencies of anti-tumor immunity inhibitory regulatory B cells (p=0.0024) but not regulatory T cells.
Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of Bregs precede the diagnosis of AIDS-NHL in HIV-infected ART-treated subjects.
PMCID: PMC4825805  PMID: 26372276
HIV; non-Hodgkin lymphoma (NHL); Toll-like receptor; regulatory B cells; microRNA; microbial translocation
AIDS (London, England)  2015;29(10):1183-1193.
To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men.
Two longitudinal studies of HIV infection in the United States.
Data from 2,549 women in the Women’s Interagency HIV Study (WIHS) and 4,274 men in the Multicenter AIDS Cohort Study (MACS), all with a history of cigarette smoking, were analyzed. Lung cancer incidence rates and incidence rate ratios were calculated using Poisson regression analyses. Survival time was assessed using Kaplan-Meier and Cox proportional hazard analyses.
Thirty-seven women and 23 men developed lung cancer (46 HIV-infected and 14 HIV-uninfected) during study follow-up. In multivariable analyses, the factors that were found to be independently associated with a higher lung cancer incidence rate ratios were older age, less education, 10 or more pack-years of smoking, and a prior diagnosis of AIDS pneumonia (vs. HIV-uninfected women). In an adjusted Cox model that allowed for different hazard functions for each cohort, a history of injection drug use was associated with shorter survival, and a lung cancer diagnosis after 2001 was associated with longer survival. In an adjusted Cox model restricted to HIV-infected participants, nadir CD4 lymphocyte cell count <200 was associated with shorter survival time.
Our data suggest that pulmonary damage and inflammation associated with HIV infection may be etiologic for the increased risk of lung cancer. Encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population.
PMCID: PMC4457511  PMID: 25888645
AIDS; HIV infection; incidence; lung cancer; survival
6.  Longitudinal Trends in Sexual Behaviors with Advancing Age and Menopause Among Women With and Without HIV-1 Infection 
AIDS and behavior  2015;19(5):931-940.
We assessed changes in self-reported sexual activity (SA) over 13 years among HIV-infected and uninfected women. The impact of aging and menopause on SA and unprotected anal or vaginal intercourse (UAVI) was examined among women in the Women’s Interagency HIV Study (WIHS), stratifying by HIV status and detectable viral load among HIV-infected women. Generalized mixed linear models were fitted for each outcome, adjusted for relevant covariates. HIV-uninfected women evidenced higher levels of SA and UAVI than HIV-infected. The odds of SA declined by 62–64 % per decade of age. The odds of SA in a 6-month interval for women aged 40–57 declined by 18–22 % post-menopause (controlling for age). Among HIV+/detectable women only, the odds of any UAVI decreased by 17 % per decade of age; the odds of UAVI were unchanged pre-menopause, and then decreased by 28 % post-menopause. Elucidating the factors accounting for ongoing unprotected sex among older women should inform interventions.
PMCID: PMC4370800  PMID: 25245474
Sexual activity; Sexual risk behaviors; Aging; Menopause; Women’s Interagency HIV Study (WIHS)
7.  Risk of Breast Cancer with CXCR4-using HIV Defined by V3-Loop Sequencing  
Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures.
A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIVgp120-V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [False-Positive-Rate (FPR 3.5) and 2% X4 cutoff], and lower stringency DS (FPR 5.75, 15% X4 cut-off). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (κ) statistics. Case-control comparisons used exact P-values and conditional logistic regression.
In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P=0.06, odds ratio 0.14, confidence interval 0.003-1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P=0.32), lower-stringency DS (16% vs 35%, P=0.18), and phenotyping (11% vs 31%, P=0.10). HIV-X4-tropism concordance was best between PS and lower-stringency DS (93%, κ=0.83). Other pairwise concordances were 82%-92% (κ=0.56-0.81). Concordance was similar among cases and controls.
HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency deep sequencing and was significantly associated with lower odds of breast cancer.
PMCID: PMC4262599  PMID: 25321183
Chemokine receptors; HIV; AIDS; breast cancer; parallel sequencing; women
8.  Long-term cumulative detection of human papillomavirus among HIV seropositive women 
AIDS (London, England)  2014;28(17):2601-2608.
To estimate the effects of infection by human immunodeficiency virus (HIV) on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV).
Retrospective assessment of prospectively collected data in a multicenter U.S. cohort.
HIV seropositive and at-risk seronegative participants in the Women's Interagency HIV Study were followed semiannually for up to 11 years. HPV typing was determined from cervicovaginal lavage specimens by polymerase chain reaction; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 were considered carcinogenic.
Among 3438 women enrolled, (2543 HIV seropositive, 895 seronegative), the cumulative detection of any HPV infection rose among HIV seropositive women from 53% at baseline to 92% at 8 years and among seronegative women from 22% to 66% (P < 0.0001 for HIV seropositive vs seronegative women). The 8-year cumulative detection of carcinogenic and noncarcinogenic HPV was 67% and 89% among HIV seropositive and 36% and 56% among seronegative women (P = 0.001 for both carcinogenic and noncarcinogenic HPV). The 8-year cumulative detection of HPV16 and HPV 18 was 15.2% and 15.0% in HIV seropositive and 6.7% and 6.1% in HIV seronegative women (P < 0.0001 for both). In multivariable regression analyses, lower CD4 count, age under 30 years, and smoking but not number of lifetime sexual partners were significant correlates of cumulative HPV detection.
More than 90% of HIV seropositive women have HPV detected during long follow-up. Rates are lower among at-risk HIV seronegative women, though most also develop HPV infections.
PMCID: PMC4289460  PMID: 25188771
Human papillomavirus; HIV in women; immunodeficiency
9.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
PMCID: PMC4155467  PMID: 25174034
10.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
The use of single-tablet ART regimens and its implications on adherence among HIV-infected women have not been well-described.
Participants were enrolled in the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen, using a case-crossover design.
15,523 person-visits, representing 1,727 women (53% black, 29% Hispanic, 25% IDU, median age 47), were included. Use of single-tablet regimens among ART users increased from 7% in 2006 to 27% in 2013; adherence increased from 78% to 85% during the same period (both p<0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted RR 1.05, 95% CI 1.03–1.08) and virologic suppression (RR 1.06, 95% CI 1.01–1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers.
Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.
PMCID: PMC3999284  PMID: 24326606
adherence; antiretroviral therapy; HIV; time factors; United States; viral load; women
12.  Serum biomarkers of immune activation and subsequent risk of non-Hodgkin B cell lymphoma among HIV-infected women 
There is increasing evidence that chronic immune activation predisposes to non-Hodgkin’s lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the U.S. who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined.
We conducted a nested case-control study within the Women’s Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3–5 years, 1–3 years, and 0–1 year prior to AIDS-NHL diagnosis (n=22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4+ T cell count, and study follow-up time (n=78). Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models.
Elevated levels of sCD27 (OR=7.21, 95% CI=2.62–19.88), sCD30 (OR=2.64, 95% CI=1.24–5.64), and CXCL13 (OR=2.56, 95% CI=1.32–4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a 2-to 4-fold increased risk of AIDS-NHL in certain subgroups, while elevated IL6 was associated with a 2-fold increased risk in the 0–1 year time-window, only.
These findings support the hypothesis that chronic B cell activation contributes to the development of AIDS-NHL in women.
sCD23, sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL.
PMCID: PMC3833437  PMID: 24045923
lymphoma; B cell; cytokines; AIDS; immune activation
13.  Illicit Drug Use, Depression and their Association with Highly Active Antiretroviral Therapy in HIV-Positive Women 
Drug and alcohol dependence  2007;89(1):74-81.
We examined the interaction of illicit drug use and depressive symptoms, and how they affect the subsequent likelihood of highly active antiretroviral therapy (HAART) use among women with HIV/AIDS.
Subjects included 1,710 HIV-positive women recruited from six sites in the U.S. including Brooklyn, Bronx, Chicago, Los Angeles, San Francisco/Bay Area, and Washington, DC. Cases of probable depression were identified using depressive symptom scores on the Centers for Epidemiologic Studies Depression Scale. Crack, cocaine, heroin, and amphetamine use were self-reported at 6-month time intervals. We conducted multivariate logistic random regression analysis of data collected during sixteen waves of semiannual interviews conducted from April 1996 through March 2004.
We found an interaction effect between illicit drug use and depression that acted to suppress subsequent HAART use, controlling for virologic and immunologic indicators, socio-demographic variables, time, and study site.
This is the first study to document the interactive effects of drug use and depressive symptoms on reduced likelihood of HAART use in a national cohort of women. Since evidence-based behavioral health and antiretroviral therapies for each of these three conditions are now available, comprehensive HIV treatment is an achievable public health goal.
PMCID: PMC4009351  PMID: 17291696
HIV; depression; HAART; drug use
14.  Changing Patterns of Anal Canal Carcinoma in the United States 
Journal of Clinical Oncology  2013;31(12):1569-1575.
Persistent human papillomavirus infection is associated with squamous cell carcinoma of the anal canal (SCCA). With changing sexual behaviors, SCCA incidence and patient demographics may also have changed in recent years.
The Surveillance, Epidemiology, and End Results public-use data set from 1973 to 2009 was analyzed to determine incidence trends for and demographic factors characterizing SCCA. Joinpoint analyses identified time points when incidence rates changed. For comparison, similar analyses were conducted for anal adenocarcinoma.
Joinpoint analyses identified 1997 as the single inflection point among 11,231 patients with SCCA, at which the slope of incidence rates statistically increased (1997 to 2009 v 1973 to 1996: risk ratio [RR], 2.2; 95% CI, 2.1 to 2.3). Annual percent change (APC) increased for all SCCA stages and was the greatest for anal carcinoma in situ (CIS; APC, 14.2; 95% CI, 10.2 to 18.4). Demographic changes characterizing later versus earlier time period included younger age at diagnosis and rising incidence rates in all stage, sex, and racial groups. During 1997 to 2009, women were less likely to present with CIS (RR, 0.3; 95% CI, 0.3 to 0.3) but more likely to present with localized (RR, 1.2; 95% CI, 1.1 to 1.3) and regional SCCA (RR, 1.5; 95% CI, 1.4 to 1.7). In contrast, adenocarcinoma APCs among 1,791 patients remained stable during this time period.
CIS and SCCA incidence increased dramatically after 1997 for men and women, although men were more likely to be diagnosed with CIS. These changes likely resulted from available screening in men and argue for efforts to identify high-risk individuals who may benefit from screening.
PMCID: PMC3753461  PMID: 23509304
15.  Pegylated Liposomal Doxorubicin, Rituximab, Cyclophosphamide, Vincristine, and Prednisone in AIDS-Related Lymphoma: AIDS Malignancy Consortium Study 047 
Journal of Clinical Oncology  2012;31(1):58-64.
Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers.
Patients and Methods
We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m2, rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy.
In 40 evaluable patients, median CD4 cells was 114/μL (range, 5 to 1,026/μL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/μL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection.
Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.
PMCID: PMC3530691  PMID: 23169503
16.  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
17.  Correlating knowledge of cervical cancer prevention and human papillomavirus with compliance after colposcopy referral 
To assess the impact of knowledge of cervical cancer biology and prevention as well as noncognitive measures on compliance with colposcopy referral in a high risk population.
Participants in a U.S. cohort of women with human immunodeficiency virus (HIV) and at risk comparison women completed behavior questionnaires and instruments measuring knowledge of cervical cancer prevention, depressive symptoms, trust in doctors, and perceived stress. Examinations including Pap tests also were conducted. Associations with compliance with resulting indicated colposcopy were assessed in multivariable models.
Of 326 women with indicated colposcopy, 222 (68%) were compliant with colposcopy referral and 104 (32%) noncompliant. In multivariable analysis, better colposcopy compliance was associated with less education (O.R. for compliance 2.24, 95% C.I. 1.12–4.51 vs more than high school), prior abnormal Pap (O.R. per prior abnormal Pap 1.08 95% C.I. 1.01–1.15), study site (O.R. for site with best vs worst compliance 16.1, 95% C.I. 2.91–88.6), and higher stress (O.R. for Perceived Stress Scale-10 score >16 vs lower 3.25, 95% C.I. 1.45–7.26).
Noncognitive factors and how sites manage abnormal Pap testing affect colposcopy compliance. Educational interventions alone are unlikely to improve colposcopy compliance in similar high-risk populations.
PMCID: PMC3760241  PMID: 22227841
HPV; cervical cancer prevention; Pap test; health education; perceived stress; HIV in women
18.  Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection 
The Journal of Infectious Diseases  2012;206(5):780-789.
Background.Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non–AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART).
Methods.A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2–4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation.
Results.Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation.
Conclusions.Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
PMCID: PMC3491747  PMID: 22693231
19.  An Investigation of the Possible Interaction between the Use of Vitamin C and Highly Active Anti-Retroviral Therapy (HAART) Adherence and Effectiveness in Treated HIV+ Women 
Our goal in this study was to examine how Vitamin C interacts with antiretroviral therapy in individuals with HIV. We specifically evaluated how Vitamin C impacts highly active antiretroviral therapy (HAART) adherence and HAART effectiveness as adjudicated by HIV viral loads and CD4 cell counts. Women served as their own controls, comparing periods of Vitamin C usage with periods of non-usage.
An intra-individual, cross-sectional comparative study ‘nested’ in the WIHS observational cohort study
Women in the Women’s Interagency HIV Study (WIHS).
Outcome Measures
Adherence, CD4 count and Viral load.
Our study population was drawn from 2,813 HIV+ participants who contributed 44,588 visits in WIHS from October, 1994 to April, 2009. Among them, there were 1,122 Vitamin C users with 4,954 total visits where use was reported. In the multivariate model adjusting for age, education, race, income, drug use, Vitamin C use order and depression score, there was a 44% increase in the odds of >=95% HAART adherence among participants during their period of Vitamin C use compared to when they were not using Vitamin C (OR=1.44; 95% CI=1.1–1.9; P-value=0.0179). There was an association with Vitamin C usage and CD4 counts on viral loads.
Vitamin C usage appears to be associated with improved adherence. Future Vitamin C studies should target specific HAART drugs, and prospective clinical outcomes.
PMCID: PMC3351689  PMID: 22579434
20.  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
21.  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
22.  Short-term Garlic Supplementation and Highly Active Antiretroviral Treatment Adherence, CD4+ Cell Counts, and Human Immunodeficiency Virus Viral Load 
Human immunodeficiency virus (HIV)–infected individuals frequently have consumed garlic, a popular complementary supplement. Researchers rarely have studied garlic’s association with antiretroviral therapies, however, even though that association is very relevant clinically.
To examine associations of supplemental use of garlic with highly active antiretroviral treatment (HAART) adherence level and HAART effectiveness (HIV viral load and CD4+ cell counts) in HIV-infected women.
The research team carried out a self-controlled, longitudinal study nested within the Women’s Interagency HIV Study (WIHS). The team used a paired study design that allowed participants to serve as their own controls. The team first identified all of the study’s visits in which the participant self-reported the use of a garlic supplement since her last visit (index visit). Then for each index visit, the team identified a matching visit (a control visit) using the following criteria: (a) the visit must be one for the same participant in which that participant reported no garlic supplementation; (b) the visit must immediately precede the index visit (less than 1 year apart); and (c) at the time of the control visit, the participant must have been using antiretroviral therapy identical to that used at the time of the index visit.
Participants were persons using garlic supplementation who already were participants in the WIHS.
Outcome Measures
The research team used a logistic regression model to examine the association between garlic supplementation and HAART adherence level. The team used a mixed linear model to examine the association of garlic supplementation with HIV viral load and CD4+ cell counts.
From October 1994 to April 2009, 390 HIV-infected women in the WIHS made 1112 visits at which they reported using garlic supplements. Seventy-seven HIV-infected women using HAART met the research team’s selection criteria and contributed 99 pairs of visits for the study. Among the women who used garlic supplements, 22% were 50 years and older; 58% were black and non-Hispanic; and 23% had less than a high-school education. Neither use of garlic supplementation nor reasons for using garlic supplements were significantly associated with the HAART adherence level, HIV viral load, or CD4+ cell counts; however, “use garlic as needed,” a potential marker of a disease state, was significantly associated with higher viral load (P = .0003).
Short-term garlic supplementation did not impact HAART adherence level, HIV viral load, and CD4+ cell counts.
PMCID: PMC3376904  PMID: 22516847
24.  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
25.  Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study 
AIDS (London, England)  2010;24(17):2679-2686.
The clinical importance of the association of HIV infection and antiretroviral therapy (ART) with low bone mineral density (BMD) in premenopausal women is uncertain because BMD stabilizes on established ART and fracture data are limited.
We measured time to first new fracture at any site with median follow-up of 5.4 years in 2391 (1728 HIV-infected, 663 HIV-uninfected) participants in the Women’s Interagency HIV Study (WIHS). Self-report of fracture was recorded at semiannual visits. Proportional hazard models assessed predictors of incident fracture.
At baseline, HIV-infected women were older (40 ± 9 vs. 36 ± 10 years, P <0.0001), more likely to report postmenopausal status and be hepatitis C virus-infected, and weighed less than HIV-uninfected women. Among HIV-infected women, mean CD4+ cell count was 482 cells/μl; 66% were taking ART. Unadjusted incidence of fracture did not differ between HIV-infected and uninfected women (1.8 vs. 1.4/100 person-years, respectively, P = 0.18). In multivariate models, white (vs. African-American) race, hepatitis C virus infection, and higher serum creatinine, but not HIV serostatus, were statistically significant predictors of incident fracture. Among HIV-infected women, older age, white race, current cigarette use, and history of AIDS-defining illness were associated with incidence of new fracture.
Among predominantly premenopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors. Further research is necessary to characterize fracture risk in HIV-infected women during and after the menopausal transition.
PMCID: PMC3108019  PMID: 20859192
fracture; fragility fracture; HIV-infected women; premenopausal

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