There is limited research examining the sexual health and well-being of older women living with HIV (OWLH). Most studies focus on sexual dysfunction, leaving aside the richer context of sexuality and sexual health, including the effect of age-related psychosocial and interpersonal changes on sexual health behaviors. Guided by the integrative biopsychosocial model and the sexual health model, this study explored the importance of sex and sexuality among OWLH to identify their sexual health and HIV prevention needs for program planning. A purposive sample ( n = 50) of OWLH was selected from a parent study ( n = 2052). We conducted 8 focus groups and 41 in-depth interviews with 50 African American and Latina OWLH aged 50–69 years old in three U.S. cities. The triangulation approach was used to synthesize the data. Six salient themes emerged: sexual pleasure changes due to age, sexual freedom as women age, the role of relationships in sexual pleasure, changes in sexual ability and sexual health needs, sexual risk behaviors, and ageist assumptions about older women’s sexuality. We found that sexual pleasure and the need for intimacy continue to be important for OWLH, but that changing sexual abilities and sexual health needs, such as the reduction of sexual desire, as well as increased painful intercourse due to menopause-associated vaginal drying, were persistent barriers to sexual fulfillment and satisfaction. Particular interpersonal dynamics, including low perceptions of the risk of HIV transmission as related to gender, viral suppression, and habitual condomless sex with long-term partners without HIV transmission have resulted in abandoning safer sex practices with serodiscordant partners. These findings suggest that HIV prevention for OWLH should focus on how sexual function and satisfaction intersect with sexual risk. HIV prevention for OWLH should promote ways to maintain satisfying and safe sex lives among aging women.

Objectives: We evaluated the Veterans Aging Cohort Study (VACS) Index score, an index composed of age, CD4 count, viral load, hemoglobin, Hepatitis C coinfection, Fibrosis Index-4, and estimated glomerular filtration rate, and psychosocial and clinical risk factors for all-cause hospitalization among HIV-infected women on highly active antiretroviral therapy and HIV-uninfected women. Methods: Data were collected from 2008 to 2014 from 1585 highly active antiretroviral therapy-experienced HIV infected and 692 uninfected women. Cox proportional hazards regression evaluated predictors of first hospitalization over 2 years. Results: Among HIV-infected women, VACS Index score (per 5 points) [adjusted hazard ratio (aHR) 1.08; 95% confidence interval (CI): 1.06 to 1.11], Centers for Epidemiologic Studies-Depression (CESD) scores ≥16 (aHR 1.61; 95% CI: 1.30 to 1.99), smoking (aHR 1.26; 95% CI: 1.02 to 1.55), abuse history (aHR 1.52; 95% CI: 1.20 to 1.93), diabetes (aHR 1.63; 95% CI: 1.31 to 2.04), and black race (aHR 1.28; 95% CI: 1.03 to 1.59) increased risk of hospitalization. Among HIV-uninfected women, VACS Index score (aHR 1.08; 95% CI: 1.03 to 1.13), CESD scores ≥16 (aHR 1.38; 95% CI: 1.02 to 1.86), diabetes (aHR 2.15; 95% CI: 1.57 to 2.95), and black race (aHR 1.61; 95% CI: 1.15 to 2.24) predicted subsequent hospitalization. Conclusions: Psychosocial and clinical factors were associated with risk of hospitalization independently of the VACS Index score. Additional research on contextual and psychosocial influences on health outcomes among women is needed.

Background: Value is defined as health outcomes achieved per dollar spent. While risk-stratified AL HCT survival estimates are made possible by the Stem Cell Therapeutic Outcomes Database (SCTOD), an assessment of healthcare value is not possible as they do not include cost adjustments based upon clinical risk. We report a risk-based cost analysis, modeled on AL pts undergoing HCT at our institution that can potentially serve as a simple, statistically significant risk-based comparison tool.

Cardiovascular disease (CVD) is increasingly common among women with HIV, but literature on nonlipid CVD risk factor management is lacking. We examined semiannual trends from 2006 to 2014 in hypertension treatment and control (blood pressure <140/90 mmHg), diabetes treatment and control (fasting glucose <130 mg/dL), and smoking quit rates in the Women's Interagency HIV Study. Unadjusted and adjusted Poisson regression models tested time trends and differences between HIV+ and HIV- women. Among antiretroviral therapy (ART) users, we examined the association of ART adherence and virologic suppression with each outcome. We evaluated 1636 HIV+ and 683 HIV- women, with a hypertension prevalence of 40% and 38%, respectively; diabetes prevalence of 21% and 22%; and smoking prevalence of 37% and 48%. Hypertension treatment was higher among HIV+ than HIV- women (77% vs. 67%, p < 0.001) and increased over time with no difference in trend by HIV status. Hypertension control was greater among HIV+ women (56% vs. 43%, p < 0.001) and increased over time among HIV+ but not HIV- women. Diabetes treatment was similar among HIV+ and HIV- women (48% vs. 49%) and increased over time in both groups. Diabetes control was greater among HIV+ women (73% vs. 64%, p = 0.03) and did not change over time. The percent of recent smokers who reported no longer smoking was similar between HIV+ and HIV- women (10% vs. 9%), with no differences over time. Virologic suppression was significantly associated with increased hypertension treatment and greater control. HIV+ women have better control of hypertension and diabetes than HIV- women, but many are still not at target levels.

The patient is a 61-year-old male with a diagnosis of relapse classical Hodgkin lymphoma, treated with ABVD, ICE, and achieved remission. He underwent autologous stem cell transplantation and 3months later found to have a PET-positive neck node concerning for relapsed disease of Hodgkin lymphoma. Biopsy proved the lesion was HPV-associated squamous cell carcinoma and not relapse Hodgkin disease. Iatrogenic immunosuppression such as bone marrow transplantation can cause substantial increase risk for viral-associated tumors and therefore tissue biopsies are necessary to make that distinction to avoid inappropriate treatment.

Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/μL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4(+) T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.

Background: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. Methods:The VACS index (based on age, CD4 count, HIV-1 RNA, hemoglobin, aspartate aminotransferase, alanine aminotransferase, platelets, creatinine, and Hepatitis C status) was validated in HIV-infected women in the Women's Interagency HIV Study (WIHS) who initiated antiretroviral therapy 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. Results:The VACS index accurately predicted 5-year mortality in 1057 WIHS women with 1 year on highly active antiretroviral therapy with c-index 0.83 [95% confidence interval (CI): 0.79 to 0.87]. In multivariate analysis, the VACS index score [adjusted hazard ratio (aHR) for a 5-point increment 1.30; 95% CI: 1.25 to 1.35], depressive symptoms (aHR 1.73; 95% CI: 1.17 to 2.56), and history of transactional sex (aHR 1.93; 95% CI: 1.33 to 1.82) were independent statistically significant predictors of mortality. Conclusions:Both 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.

OBJECTIVES:To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men.DESIGN:Two longitudinal studies of HIV infection in the United States.METHODS:Data from 2549 women in the Women's Interagency HIV Study (WIHS) and 4274 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.RESULTS: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 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 less than 200 was associated with shorter survival time.CONCLUSIONS:Our data suggest that pulmonary damage and inflammation associated with HIV infection may be causative 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.

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.

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.

Objectives: In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells. Design: A case–control study nested with a cohort study of HIV-infected women. Methods: Prediagnostic AIDS-NHL cases (n = 12, collected 1–12 months before diagnosis) and controls (n = 42) from the Women's Interagency HIV Study 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/germinal center-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. Results: Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19+CD10+CD71+CD86+AID+ B cells (P = 0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P = 0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho = 0.7273, P = 0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P = 0.0024), but not regulatory T cells. Conclusions: Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.

Objective: Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures.Methods: 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. HIV-gp120 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 (3.5) and 2% X4 cutoff], and lower stringency DS (false-positive rate, 5.75 and 15% X4 cutoff). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (k) statistics. Case-control comparisons used exact P values and conditional logistic regression.Results: 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 to 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%, k = 0.83). Other pairwise concordances were 82%-92% (k = 0.56-0.81). Concordance was similar among cases and controls.Conclusions: HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency DS and was significantly associated with lower odds of breast cancer.

Academic cancer centers play a vital role in cancer care in an increasingly cost-sensitive health care market, and proponents must emphasize the value-based clinical, research, and business contributions these centers can make to the eradication of cancer.

Objective:To estimate the effects of infection by HIV on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV). Design:Retrospective assessment of prospectively collected data in a multicenter US cohort. Methods: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 PCR; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 were considered carcinogenic. Results:Among the 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 HPV18 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+ cell count, age under 30 years, and smoking, but not number of lifetime sexual partners, were significant correlates of cumulative HPV detection. Conclusion:More than 90% of the HIV-seropositive women have HPV detected during a long follow-up. The rates are lower among at-risk HIV-seronegative women, though most also develop HPV infections.

Abstract TLR2-signaling may contribute to B-cell activation during HIV infection leading to HIV-NHL genesis; a common malignancy in anti-retroviral therapy (ART) treated patients. TLR-signaling and anti-tumor immunity inhibitory regulatory B cells (Bregs) contribute to lymphomagenesis but their roles in HIV-NHL genesis remain unexplored. We investigated, if in HIV- donors, TLR-activated B cells mimic an activated/germinal center (GC)-like phenotype aberrantly expressed in B-cell lymphomas. Further, in HIV+ART subjects: (cases = <1 year pre-NHL, controls = HIV+ART but don’t develop NHL), we assessed: 1) B-cell TLR2 and TLR2 modulatory miRNA expression 2) Breg frequency and 3) serum levels of TLR-ligands. In B cells from HIV- donors only TLR2- (unlike TLR4 nor 9) stimulation (p=0.03), leads to an aberrant phenotype (CD10+CD71+CD86+AID+) identified in lymphomas. Compared to controls, cases exhibit significantly elevated: 1) frequency of CD10+CD71+CD86+AID+ B cells (p=0.01) and Bregs (p=0.0071), 2) serum levels of TLR2 and TLR9 ligands (lipoteichoic acid, p=0.03 and 16s DNA, p=0.03 respectively), 3) B-cell TLR2 expression (p=0.0024). Finally, in cases, the activated/GC-like cells exhibit dysregulation of miRNA regulating TLR2-expression including miR-9, miR-19a and miR146a. Our data suggest that HIV-NHL genesis is associated with aberrant GC-like B cells, elevated Bregs and a possible role for TLR2-stimulation.

Objective:Plasma HIV RNA levels have been associated with the 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. Design/Methods:In an HIV-seropositive women's cohort with semiannual 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 (HSIL) subclassified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incidents of severe HSIL were matched to 130 controls by age, CD4+ count, highly active antiretroviral therapy use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects. Results: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, 2.96; 95% confidence interval: 0.99 to 8.84; Ptrend = 0.03). However, this association became nonsignificant (Ptrend = 0.51) after 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. Conclusions:These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical precancer in HIV-seropositive women, but they leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumorigenesis.

Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.

BACKGROUND: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.METHODS: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).RESULTS: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.CONCLUSIONS: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.