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1.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2012.42.4648
PMCID: PMC3530691  PMID: 23169503
2.  Changing Patterns of Anal Canal Carcinoma in the United States 
Journal of Clinical Oncology  2013;31(12):1569-1575.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2012.45.2524
PMCID: PMC3753461  PMID: 23509304
3.  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
4.  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
5.  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.
doi:10.1093/infdis/jis380
PMCID: PMC3491747  PMID: 22693231
6.  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 
Objectives
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.
Design
An intra-individual, cross-sectional comparative study ‘nested’ in the WIHS observational cohort study
Subjects
Women in the Women’s Interagency HIV Study (WIHS).
Outcome Measures
Adherence, CD4 count and Viral load.
Results
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.
Conclusion
Vitamin C usage appears to be associated with improved adherence. Future Vitamin C studies should target specific HAART drugs, and prospective clinical outcomes.
doi:10.1016/j.ctim.2012.03.001
PMCID: PMC3351689  PMID: 22579434
7.  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
8.  Factors Associated with Prevalent Hepatitis C Infection Among HIV-Infected Women with No Reported History of Injection Drug Use: The Women’s Interagency HIV Study (WIHS) 
AIDS patient care and STDs  2009;23(11):915-923.
Although the primary mode of hepatitis C virus (HCV) transmission is exposure to blood products or injection drug use (IDU), studies have found varying independent risk factors for HCV infection among persons with no history of IDU or exposure to blood products. For HIV-infected women, sexual transmission may be another potential source of HCV infection. HIV-infected and HIV-negative women at risk for HIV enrolled in the Women’s Interagency HIV Study (WIHS) during October 1994 to November 1995 and again between October 2001 and November 2002 were studied. Clinical and demographic factors associated with HCV seroprevalence were assessed in multivariate logistic regression models controlling for history of blood transfusion and IDU. Among 3636 women with HCV results, 31.5% were HCV antibody positive (HCV+) including 13.5% with no reported history of IDU or blood transfusions. Multivariate logistic regression analyses stratified on IDU showed that among women with no history of IDU, sex with an IDU male was independently associated with HCV positivity (odds ratio [OR] = 2.8, 95% confidence [CI] = 2.1, 3.8, p < 0.0001) after controlling for blood transfusion, age, HIV infection, unemployment, birth in the United States, history of hepatitis B infection, and current smoking status. Further stratification on HIV status showed that the association was significant only for the HIV+ (OR = 1.9, 95% CI = 1.3, 2.7, p = 0.0007) compared to the HIV− women (OR = 1.1, 95% CI = 0.4, 2.7) although these odds ratios were not significantly different ( p = 0.25). For HIV-positive women with no reported history of IDU, sex with an IDU male was independently associated with HCV suggesting that sexual transmission may be an important mode of HCV transmission for these high-risk women.
doi:10.1089/apc.2009.0111
PMCID: PMC2823487  PMID: 19877800
9.  Short-term Garlic Supplementation and Highly Active Antiretroviral Treatment Adherence, CD4+ Cell Counts, and Human Immunodeficiency Virus Viral Load 
Context
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.
Objective
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.
Design
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
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.
Results
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).
Conclusion
Short-term garlic supplementation did not impact HAART adherence level, HIV viral load, and CD4+ cell counts.
PMCID: PMC3376904  PMID: 22516847
10.  Relationship Between Complementary/Alternative Treatment Use and Illicit Drug Use Among a Cohort of Women with, or at Risk for, HIV Infection 
Abstract
Objectives
Two of the most pressing public health challenges in the United States are treating human immunodeficiency virus (HIV) infection and illegal substance use. High rates of complementary and alternative medicine (CAM) use have been reported by individuals who suffer from both of these diseases. The goal of this study was to examine the relationship between CAM use and illegal substance use in a cohort of women with HIV or at risk for HIV disease. Based on previous research, it was hypothesized that CAM use may decrease substance use.
Design
This was a longitudinal cohort study.
Subjects
The subjects comprised Women in the Women's Interagency HIV Study.
Outcome measures
The role of CAM use in illegal substance use was examined. Due to the hierarchical structure of the dataset, logistic regression analysis adjusting for repeated measurements (generalized estimating equation model) was carried out to assess associations of CAM use and illicit drug use.
Results
There were 2176 women included in the analysis. After excluding for marijuana use, CAM use was associated with less drug use (odds ratio 0.82; 95% confidence interval: 0.73, 0.90).
Conclusions
The results supported our hypothesis that CAM users are more health conscious and thus less likely to use illicit drugs. Future studies should target both specific drugs and CAM modalities to help finalize this association.
doi:10.1089/acm.2009.0584
PMCID: PMC3110837  PMID: 20738164
11.  Cervical Shedding of HIV-1 RNA Among Women With Low Levels of Viremia While Receiving Highly Active Antiretroviral Therapy 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/01.qai.0000248352.18007.1f
PMCID: PMC3126662  PMID: 17106279
compartmentalization; genital; HIV; nonnucleoside reverse transcriptase inhibitor; protease inhibitor; undetectable; viral replication; women
12.  Knowledge of cervical cancer prevention and human papillomavirus among women with HIV 
Gynecologic oncology  2010;117(1):70-76.
Objective
To assess knowledge of and attitudes towards human papillomavirus (HPV), Pap testing, and the HPV vaccine.
Methods
In a multicenter U.S. cohort study, women with the human immunodeficiency virus (HIV) and at-risk comparison women completed 44-item standardized self-report questionnaires exploring their knowledge of cervical cancer prevention, HPV, and HPV vaccination. Results were correlated with demographic variables, measures of education and attention, and medical factors. Data were clustered using principal component analysis. Significant associations were assessed in multivariable models.
Results
Among 1588 women, HIV seropositive women better understood facts about cervical cancer prevention and HPV than seronegative women, but both had substantial knowledge deficits. Almost all women considered Pap testing important, although 53% of HIV seropositive and 48% of seronegative women considered cervical cancer not preventable (P=0.21). Only 44% of HIV seropositive women knew Paps assess the cervix, versus 42% of HIV seronegative women (P=0.57). Both groups understood that HPV causes genital warts and cervical cancer (67% of HIV seropositive vs. 55% of seronegative women, P=0.002). About half of both groups considered HPV vaccination extremely important for cervical cancer prevention. HIV seronegative women were more likely to report learning of HPV vaccination through advertising than from clinicians (81% vs. 64%, P<0.0001).
Conclusion
High risk women need effective education about cervical cancer prevention, HPV, and HPV vaccination.
doi:10.1016/j.ygyno.2009.12.030
PMCID: PMC3100195  PMID: 20106513
HPV; Cervical cancer prevention; Pap test; Health education; HIV in women
13.  HIV As a Risk Factor for Lung Cancer in Women: Data From the Women's Interagency HIV Study 
Journal of Clinical Oncology  2010;28(9):1514-1519.
Purpose
Prior reports of an increased risk of lung cancer in HIV-infected individuals have not always included control groups, nor considered other risk factors such as tobacco exposure. We sought to determine the role of HIV infection and highly active antiretroviral therapy (HAART) on lung cancer incidence in 2,651 HIV-infected and 898 HIV-uninfected women from the Women's Interagency HIV Study (WIHS).
Methods
A prospective study of the incidence rates of lung cancer was conducted, with cases identified through medical records, death certificates, and state cancer registries. Standardized incidence ratios (SIRs) were calculated to compare lung cancer incidence among HIV-infected and uninfected WIHS participants, with population-based expectations using the Surveillance, Epidemiology, and End Results registry. Behavioral characteristics in the WIHS were compared to US women by age and race adjusting the population-based data from the National Health and Nutritional Examination Survey (NHANES) III.
Results
Incidence rates of lung cancer were similar among HIV-infected and uninfected WIHS women. Lung cancer SIRs were increased in both HIV-infected and -uninfected women compared with population expectations, but did not differ by HIV status. Among HIV-infected women, lung cancer incidence rates were similar in pre-HAART and HAART eras. All WIHS women with lung cancer were smokers; the risk of lung cancer increased with cumulative tobacco exposure. WIHS women were statistically more likely to smoke than US women studied in NHANES III.
Conclusion
HIV infection is strongly associated with smoking behaviors that increase lung cancer risk. The role of HIV itself remains to be clarified.
doi:10.1200/JCO.2009.25.6149
PMCID: PMC2849771  PMID: 20177022
14.  Influence of Adherent and Effective Antiretroviral Therapy Use on Human Papillomavirus Infection and Squamous Intraepithelial Lesions in HIV-Positive Women 
Background
The impact of HAART on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients’ adherence to their regimen, or HAART effectiveness (viral suppression).
Methods
HIV-positive women (N=286) who initiated HAART during follow-up in a prospective cohort were assessed semiannually for HPV (by PCR) and SIL. Adherence was defined as using HAART as prescribed ≥95% of the time, and effective HAART as suppression of HIV replication. The prevalence, incident detection, clearance/persistence of HPV/SIL before versus after HAART initiation were compared (using women as their own comparison group).
Findings
HAART initiation among adherent women was associated with a significant reduction in prevalence (odds ratio [OR] 0.60 [95% CI 0.44–0.81];p=0.001), incident detection of oncogenic HPV (hazard ratio [HR] 0.49 [0.30–0.82];p=0.006), and decreased prevalence and more rapid clearance of oncogenic HPV-positive SIL (HR 2.35 [1.07–5.18];p=0.03). Effects were smaller among non-adherent women. The associations of HPV/SIL with HAART effectiveness were fairly similar to those with HAART adherence.
Conclusions
Effective and adherent HAART use is associated with a significantly reduced burden of HPV and SIL; this may help explain why rates of cervical cancer have not increased during the HAART era, despite greater longevity.
doi:10.1086/650467
PMCID: PMC2818607  PMID: 20105077
HIV; human papillomavirus; HPV; HAART; SIL; cervical neoplasia
15.  Histologic Correlates of Glandular Abnormalities in Cervical Cytology Among Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2009;114(5):1063-1068.
Objective
To estimate the frequency and histologic correlates of glandular abnormalities in cervical cytology among women with the human immunodeficiency virus and to compare findings with those of women without HIV.
Methods
In a cohort study of HIV infected and uninfected women followed between 1994 and 2007, Pap tests were obtained every 6 months. Glandular abnormalities, including atypical glandular cells (AGC), adenocarcinoma in situ (AIS), and adenocarcinoma, were identified and correlated with biopsy histology. Multivariate models to summarize data across visits used Generalized Estimating Equations. The association of Pap and histology results was assessed using chi-square tests.
Results
Of 48,362 Pap tests from 3,766 women, glandular abnormalities were found in 341 (0.7%) smears from 244 (6%) women, including 93 (1.0%) of 9,564 Pap tests among HIV-seropositive women with CD4 lymphocyte counts less than 250/cmm, 103 (0.8%) of 13,023 Paps among those with counts 250–500/cmm, 68 (0.6%) of 12,470 Paps among women with counts greater than 500/cmm, and 70 (0.6%) of 11,769 Paps among HIV-seronegative women (P for trend = 0.006). Colposcopy was documented for only 148 (61%) of 244 index Pap tests in women with glandular abnormalities. After index abnormal Paps, endocervical curettings were obtained from 106 (43%) women, cervical biopsies from 76 (38%), and endometrial biopsies from 19 (8%). Squamous lesions predominated among histologic findings and histology results did not differ by HIV serostatus (P = 0.16).
Conclusion
Although immunosuppression increased the risk of glandular Pap abnormalities increased in women with HIV, these remained uncommon. Compliance with management guidelines can improved.
doi:10.1097/AOG.0b013e3181bc6ce0
PMCID: PMC3032588  PMID: 20168108
16.  Marginal and Mixed Effects Models in the Analysis of HPV Natural History Data 
Human papillomavirus (HPV) natural history has several characteristics that, at least from a statistical perspective, are not often encountered elsewhere in infectious disease and cancer research. There are, for example, multiple HPV types, and infection by each HPV type may be considered separate events. While concurrent infections are common, the prevalence, incidence, duration/persistence of each individual HPV can be separately measured. However, repeated measures involving the same subject tend to be correlated. The probability of detecting any given HPV type, for example, is greater among individuals who are currently positive for at least one other HPV type. Serial testing for HPV over time represents a second form of repeated measures. Statistical inferences that fail to take these correlations into account would be invalid. However, methods that do not use all the data would be inefficient. Marginal and mixed effects models can address these issues, but are not frequently utilized in HPV research. The current paper provides an overview of these methods, and then uses HPV data from a cohort of HIV-positive women to illustrate how they may be applied, and compare their results. The findings show the greater efficiency of these models compared with standard logistic regression and Cox models. Because mixed effects models estimate subject-specific associations, they sometimes gave much higher effect estimates than marginal models, which estimate population-averaged associations. Overall, the results demonstrate that marginal and mixed effects models are efficient for studying HPV natural history, but also highlight the importance of understanding how these models differ.
doi:10.1158/1055-9965.EPI-09-0546
PMCID: PMC2839537  PMID: 20056635
statistical methods; cervical neoplasia; human papillomavirus; HPV; HIV; frailty models; mixed effects models; WLW models; frailty models
17.  Trends in Mortality and Causes of Death among Women with HIV in the US: A Ten-year Study 
Background
To assess trends in mortality and cause of death for women with HIV, we studied deaths over a 10 year period among participants in the Women’s Interagency HIV Study (WIHS), a representative US cohort.
Methods
Deaths were ascertained by National Death Index-Plus match and causes of death determined by death certificate.
Results
From 1995 through 2004, 710 of 2792 HIV-infected participants died. During this interval the standardized mortality ratio (SMR) fell from a high of 24.7 in 1996 to a plateau with a mean of 10.3 from 2001–2004. Over the decade, deaths from non-AIDs causes increased and accounted for the majority of deaths by 2001–2004. The most common non-AIDS causes of death were trauma or overdose, liver disease, cardiovascular disease and malignancy. Independent predictors of mortality besides HIV-associated variables were depressive symptoms, and active hepatitis B or C. Women who were overweight or obese were significantly less likely to die of AIDS than women of normal weight.
Conclusion
In the WIHS, the death rate has plateaued in recent years. While HIV-associated factors predicted AIDS and non-AIDS deaths, other treatable conditions predicted mortality. Further gains in reducing mortality among HIV-infected women may require broader access to therapies for depression, viral hepatitis and HIV itself.
doi:10.1097/QAI.0b013e3181acb4e5
PMCID: PMC2769934  PMID: 19487953
HIV; mortality; women; viral hepatitis; non-AIDs mortality
18.  Antiretroviral Therapy Exposure and Insulin Resistance in the Women’s Interagency HIV Study 
Background
Evidence suggesting an increased risk of cardiovascular disease in HIV-infected individuals has heightened the need to understand the relation of HIV infection, antiretroviral therapy use, and non–HIV-related factors with insulin resistance (IR).
Methods
Prospective study of 1614 HIV-infected and 604 HIV-uninfected participants from the Women’s Interagency HIV Study between October 2000 and March 2007. Homeostasis model assessment (HOMA)–estimated IR at 11,019 semiannual visits.
Results
HIV-infected women reporting highly active antiretroviral therapy (HAART) had higher median HOMA than HIV-uninfected women {1.20 [95% confidence interval (CI): 1.11 to 1.30] times higher for those reporting protease inhibitor–containing HAART; 1.10 (95% CI: 1.01 to 1.20) times higher for those reporting non–protease inhibitor–containing HAART}. Among HIV-infected, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTIs) of >3 years was associated with HOMA 1.13 (95% CI: 1.02 to 1.25) times higher than the HOMA without any cumulative NRTI exposure. Cumulative exposure to the NRTI stavudine of >1 year was associated with HOMA 1.15 (95% CI: 1.05 to 1.27) times higher than the HOMA without any cumulative stavudine use. Family history of diabetes, hepatitis C virus seropositivity, higher body mass index, or reporting menopause was associated with higher HOMA.
Conclusions
Longer cumulative exposure to NRTI; in particular, stavudine is associated with greater IR in HIV-infected women.
PMCID: PMC2889144  PMID: 19186350
antiretroviral therapy; HIV; HOMA; insulin resistance; nucleoside reverse transcriptase inhibitor; protease inhibitor
19.  Effects of Chemotherapy in AIDS-Associated Non-Hodgkin's Lymphoma on Kaposi's Sarcoma Herpesvirus DNA in Blood 
Journal of Clinical Oncology  2009;27(15):2496-2502.
Purpose
To determine the relative frequency with which Kaposi's sarcoma–associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA.
Patients and Methods
Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected.
Results
In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma.
Conclusion
KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.
doi:10.1200/JCO.2008.20.1707
PMCID: PMC2684854  PMID: 19349542
20.  Long-term incidence of cervical cancer in women with HIV 
Cancer  2009;115(3):524-530.
Objective
To estimate the incidence of invasive cervical cancer (ICC) in women with human immunodeficiency virus (HIV) and compare it to that in HIV-uninfected women.
Methods
In a cohort study of HIV infected and uninfected women who had Pap tests obtained every six months, pathology reports were retrieved for women with biopsy or self-report of ICC. Histology was reviewed when reports confirmed ICC. Incidence rates were calculated and compared to those in HIV-negative women.
Results
After a median follow-up of 10.3 years, three ICCs were confirmed in HIV seropositive women, none in seronegative women. The ICC incidence rate was not significantly associated with HIV status (HIV negative: 0/100,000 person-years vs. HIV positive: 21.4/100,000 person-years; p=0.59). A calculated incidence rate ratio standardized to expected results from the Surveillance Epidemiology and End Results database restricted to the HIV-infected WIHS participants was 1.32 (95% CI: 0.27, 3.85; p=0.80).
Conclusion
Among women with HIV in a prospective study incorporating cervical cancer prevention measures, ICC incidence was not significantly higher than in a comparison group of HIV-negative women.
doi:10.1002/cncr.24067
PMCID: PMC2641995  PMID: 19127538
Cervical cancer; HIV in women; cancer prevention
21.  The Relationship between Cocaine Use and Human Papillomavirus Infections in HIV-Seropositive and HIV-Seronegative Women 
Objective. Animal data suggest that cocaine has an immunosuppressive effect, but no human studies have been conducted to assess the relation of cocaine use with human papillomavirus (HPV) infection, the viral cause of cervical cancer. Since both cocaine use and HPV infection are common among HIV-positive women, we sought to determine whether use of cocaine and/or crack influences the natural history of HPV among women with or at high risk of HIV. Methods. Women enrolled in the Women's Interagency HIV Study (2278 HIV-seropositive and 826 high-risk seronegative women) were examined every six months for up to 9.5 years with Pap smear, collection of cervicovaginal lavage (CVL) samples, and detailed questionnaires regarding health and behavior, including use of crack and cocaine (crack/cocaine). CVLs were tested for HPV DNA by PCR, with genotyping for over forty HPV types. Results. In multivariate logistic regression models, censoring women treated for cervical neoplasia, crack/cocaine use within the last six months was associated with prevalent detection of oncogenic HPV DNA (odds ratio [OR] = 1.30 (1.09–1.55)), and with oncogenic HPV-positive squamous intraepithelial lesions (SIL) (OR = 1.70 (1.27–2.27)), following adjustment for age, race, HIV-serostatus, and CD4+ T-cell count, the number of sexual partners in the past six months, and smoking. In multivariate Cox models crack/cocaine use was also associated with a trend that approached significance in regard to incident detection of oncogenic HPV-positive SIL (HR = 1.51, 95% CI 0.99–2.30), and while the rate of oncogenic HPV clearance was not related to cocaine use, the clearance of any SIL was significantly lower in those with versus those without recent crack/cocaine use (HR = 0.57, 95% CI 0.34–0.97). Conclusions. Cocaine use is associated with an increased risk of detection of both prevalent and incident oncogenic HPV infection, as well as an increased risk of HPV-positive SIL over time.
doi:10.1155/2008/587082
PMCID: PMC2324195  PMID: 18437233
22.  Serological Detection of Human Papillomavirus Type 16 Infection in Human Immunodeficiency Virus (HIV)-Positive and High-Risk HIV-Negative Women 
Clinical and Vaccine Immunology  2006;13(4):511-519.
Serial measurement of antibodies has not been used to provide evidence of active viral replication of human papillomavirus (HPV). Serum specimens from sequential study visits contributed by 642 human immunodeficiency virus (HIV)-positive and 116 HIV-negative participants enrolled in the Women's Interagency HIV Study were used to detect significant rises in HPV type 16 (HPV-16) antibody levels. Factors associated with a significant rise were identified using multivariable logistic regression models with generalized estimating equations. Among HIV-positive women, 8.3% of 1,997 pairs showed antibody rises, compared to 6.1% of 361 pairs among HIV-negative women (P = 0.191). For HIV-positive women, rises were associated with current (odds ratio [OR], 23.4; P < 0.001) or past (OR, 8.9; P < 0.001) HPV-16 infection relative to never being HPV-16 infected and with CD4+ cell counts (OR per 100-cell increase, 0.8; P < 0.001) but not with sexual behavior. For HIV-negative women, rises were associated with past (OR, 10.9; P = 0.033) HPV-16 infection relative to no HPV-16, current cigarette smoking (OR, 5.0; P = 0.029) relative to no smoking history, and having 6 to 10 lifetime sexual partners compared to 0 to 5 partners (OR, 9.9; P = 0.036). Serial measurement of HPV-16 serum antibodies is a useful tool for identifying active HPV-16 viral replication. Rises among HIV-positive women may more often result from reactivation of a latent HPV infection in the context of HIV-induced immunosuppression, while rises among HIV-negative women may more often result from reinfection with HPV.
doi:10.1128/CVI.13.4.511-519.2006
PMCID: PMC1459636  PMID: 16603621
23.  Hepatitis C Virus Induces Toll-Like Receptor 4 Expression, Leading to Enhanced Production of Beta Interferon and Interleukin-6 
Journal of Virology  2006;80(2):866-874.
Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-β) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-β and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.
doi:10.1128/JVI.80.2.866-874.2006
PMCID: PMC1346849  PMID: 16378988
24.  Hepatitis C Virus Infection Activates the Immunologic (Type II) Isoform of Nitric Oxide Synthase and Thereby Enhances DNA Damage and Mutations of Cellular Genes 
Journal of Virology  2004;78(16):8835-8843.
Hepatitis C virus (HCV) infection causes hepatitis, hepatocellular carcinoma, and B-cell lymphomas in a significant number of patients. Previously we have shown that HCV infection causes double-stranded DNA breaks and enhances the mutation frequency of cellular genes, including proto-oncogenes and immunoglobulin genes. To determine the mechanisms, we studied in vitro HCV infection of cell culture. Here we report that HCV infection activated the immunologic (type II) isoform of nitric oxide (NO) synthase (NOS), i.e., inducible NOS (iNOS), thereby inducing NO, which in turn induced DNA breaks and enhanced the mutation frequencies of cellular genes. Treatment of HCV-infected cells with NOS inhibitors or small interfering RNA specific for iNOS abolished most of these effects. Expression of the core protein or nonstructural protein 3 (NS3), but not the other viral proteins, in B cells or hepatocytes induced iNOS and DNA breaks, which could be blocked by NOS inhibitors. The core protein also enhanced the mutation frequency of cellular genes in hepatocytes derived from HCV core transgenic mice compared with that in control mice. The iNOS promoter was activated more than fivefold in HCV-infected cells, as revealed by a luciferase reporter assay driven by the iNOS promoter. Similarly, the core and NS3 proteins also induced the same effects. Therefore, we conclude that HCV infection can stimulate the production of NO through activation of the gene for iNOS by the viral core and NS3 proteins. NO causes DNA breaks and enhances DNA mutation. This sequence of events provides a mechanism for HCV pathogenesis and oncogenesis.
doi:10.1128/JVI.78.16.8835-8843.2004
PMCID: PMC479064  PMID: 15280491
25.  Establishment of B-Cell Lymphoma Cell Lines Persistently Infected with Hepatitis C Virus In Vivo and In Vitro: the Apoptotic Effects of Virus Infection 
Journal of Virology  2003;77(3):2134-2146.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.
doi:10.1128/JVI.77.3.2134-2146.2003
PMCID: PMC140883  PMID: 12525648

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