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1.  A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African-American women 
Addiction biology  2010;17(1):181-191.
Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size - no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek-McHugh-Schluger-Kellogg (KMSK) scales for alcohol, cocaine, opiates, and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 HIV-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study (WIHS), an ongoing study of HIV in women. Forty-two of 697 African-American, 1 of 182 Hispanic, and none of 161 white women had the TT genotype. KMSK cocaine, alcohol, and tobacco scores were significantly higher in African-American women with the TT genotype (p =0.008, 0.0001, and 0.006 respectively) but opiate scores were not. Ordinal regression models controlling for HIV-serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine, and opiates scores of 2.1 (p = 0.02), 2.4 (p = 0.0004), 2.0 (p = 0.03), and 1.9 (p = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.
doi:10.1111/j.1369-1600.2010.00265.x
PMCID: PMC3117061  PMID: 21070507
C17T polymorphism; HIV; mu opioid receptor gene; quantitative measures; substance abuse; substance dependence
2.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
Methods
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
Results
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Conclusions
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
3.  The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation 
Pereyra, Florencia | Jia, Xiaoming | McLaren, Paul J. | Telenti, Amalio | de Bakker, Paul I.W. | Walker, Bruce D. | Jia, Xiaoming | McLaren, Paul J. | Ripke, Stephan | Brumme, Chanson J. | Pulit, Sara L. | Telenti, Amalio | Carrington, Mary | Kadie, Carl M. | Carlson, Jonathan M. | Heckerman, David | de Bakker, Paul I.W. | Pereyra, Florencia | de Bakker, Paul I.W. | Graham, Robert R. | Plenge, Robert M. | Deeks, Steven G. | Walker, Bruce D. | Gianniny, Lauren | Crawford, Gabriel | Sullivan, Jordan | Gonzalez, Elena | Davies, Leela | Camargo, Amy | Moore, Jamie M. | Beattie, Nicole | Gupta, Supriya | Crenshaw, Andrew | Burtt, Noël P. | Guiducci, Candace | Gupta, Namrata | Carrington, Mary | Gao, Xiaojiang | Qi, Ying | Yuki, Yuko | Pereyra, Florencia | Piechocka-Trocha, Alicja | Cutrell, Emily | Rosenberg, Rachel | Moss, Kristin L. | Lemay, Paul | O’Leary, Jessica | Schaefer, Todd | Verma, Pranshu | Toth, Ildiko | Block, Brian | Baker, Brett | Rothchild, Alissa | Lian, Jeffrey | Proudfoot, Jacqueline | Alvino, Donna Marie L. | Vine, Seanna | Addo, Marylyn M. | Allen, Todd M. | Altfeld, Marcus | Henn, Matthew R. | Le Gall, Sylvie | Streeck, Hendrik | Walker, Bruce D. | Haas, David W. | Kuritzkes, Daniel R. | Robbins, Gregory K. | Shafer, Robert W. | Gulick, Roy M. | Shikuma, Cecilia M. | Haubrich, Richard | Riddler, Sharon | Sax, Paul E. | Daar, Eric S. | Ribaudo, Heather J. | Agan, Brian | Agarwal, Shanu | Ahern, Richard L. | Allen, Brady L. | Altidor, Sherly | Altschuler, Eric L. | Ambardar, Sujata | Anastos, Kathryn | Anderson, Ben | Anderson, Val | Andrady, Ushan | Antoniskis, Diana | Bangsberg, David | Barbaro, Daniel | Barrie, William | Bartczak, J. | Barton, Simon | Basden, Patricia | Basgoz, Nesli | Bazner, Suzane | Bellos, Nicholaos C. | Benson, Anne M. | Berger, Judith | Bernard, Nicole F. | Bernard, Annette M. | Birch, Christopher | Bodner, Stanley J. | Bolan, Robert K. | Boudreaux, Emilie T. | Bradley, Meg | Braun, James F. | Brndjar, Jon E. | Brown, Stephen J. | Brown, Katherine | Brown, Sheldon T. | Burack, Jedidiah | Bush, Larry M. | Cafaro, Virginia | Campbell, Omobolaji | Campbell, John | Carlson, Robert H. | Carmichael, J. Kevin | Casey, Kathleen K. | Cavacuiti, Chris | Celestin, Gregory | Chambers, Steven T. | Chez, Nancy | Chirch, Lisa M. | Cimoch, Paul J. | Cohen, Daniel | Cohn, Lillian E. | Conway, Brian | Cooper, David A. | Cornelson, Brian | Cox, David T. | Cristofano, Michael V. | Cuchural, George | Czartoski, Julie L. | Dahman, Joseph M. | Daly, Jennifer S. | Davis, Benjamin T. | Davis, Kristine | Davod, Sheila M. | Deeks, Steven G. | DeJesus, Edwin | Dietz, Craig A. | Dunham, Eleanor | Dunn, Michael E. | Ellerin, Todd B. | Eron, Joseph J. | Fangman, John J.W. | Farel, Claire E. | Ferlazzo, Helen | Fidler, Sarah | Fleenor-Ford, Anita | Frankel, Renee | Freedberg, Kenneth A. | French, Neel K. | Fuchs, Jonathan D. | Fuller, Jon D. | Gaberman, Jonna | Gallant, Joel E. | Gandhi, Rajesh T. | Garcia, Efrain | Garmon, Donald | Gathe, Joseph C. | Gaultier, Cyril R. | Gebre, Wondwoosen | Gilman, Frank D. | Gilson, Ian | Goepfert, Paul A. | Gottlieb, Michael S. | Goulston, Claudia | Groger, Richard K. | Gurley, T. Douglas | Haber, Stuart | Hardwicke, Robin | Hardy, W. David | Harrigan, P. Richard | Hawkins, Trevor N. | Heath, Sonya | Hecht, Frederick M. | Henry, W. Keith | Hladek, Melissa | Hoffman, Robert P. | Horton, James M. | Hsu, Ricky K. | Huhn, Gregory D. | Hunt, Peter | Hupert, Mark J. | Illeman, Mark L. | Jaeger, Hans | Jellinger, Robert M. | John, Mina | Johnson, Jennifer A. | Johnson, Kristin L. | Johnson, Heather | Johnson, Kay | Joly, Jennifer | Jordan, Wilbert C. | Kauffman, Carol A. | Khanlou, Homayoon | Killian, Robert K. | Kim, Arthur Y. | Kim, David D. | Kinder, Clifford A. | Kirchner, Jeffrey T. | Kogelman, Laura | Kojic, Erna Milunka | Korthuis, P. Todd | Kurisu, Wayne | Kwon, Douglas S. | LaMar, Melissa | Lampiris, Harry | Lanzafame, Massimiliano | Lederman, Michael M. | Lee, David M. | Lee, Jean M.L. | Lee, Marah J. | Lee, Edward T.Y. | Lemoine, Janice | Levy, Jay A. | Llibre, Josep M. | Liguori, Michael A. | Little, Susan J. | Liu, Anne Y. | Lopez, Alvaro J. | Loutfy, Mono R. | Loy, Dawn | Mohammed, Debbie Y. | Man, Alan | Mansour, Michael K. | Marconi, Vincent C. | Markowitz, Martin | Marques, Rui | Martin, Jeffrey N. | Martin, Harold L. | Mayer, Kenneth Hugh | McElrath, M. Juliana | McGhee, Theresa A. | McGovern, Barbara H. | McGowan, Katherine | McIntyre, Dawn | Mcleod, Gavin X. | Menezes, Prema | Mesa, Greg | Metroka, Craig E. | Meyer-Olson, Dirk | Miller, Andy O. | Montgomery, Kate | Mounzer, Karam C. | Nagami, Ellen H. | Nagin, Iris | Nahass, Ronald G. | Nelson, Margret O. | Nielsen, Craig | Norene, David L. | O’Connor, David H. | Ojikutu, Bisola O. | Okulicz, Jason | Oladehin, Olakunle O. | Oldfield, Edward C. | Olender, Susan A. | Ostrowski, Mario | Owen, William F. | Pae, Eunice | Parsonnet, Jeffrey | Pavlatos, Andrew M. | Perlmutter, Aaron M. | Pierce, Michael N. | Pincus, Jonathan M. | Pisani, Leandro | Price, Lawrence Jay | Proia, Laurie | Prokesch, Richard C. | Pujet, Heather Calderon | Ramgopal, Moti | Rathod, Almas | Rausch, Michael | Ravishankar, J. | Rhame, Frank S. | Richards, Constance Shamuyarira | Richman, Douglas D. | Robbins, Gregory K. | Rodes, Berta | Rodriguez, Milagros | Rose, Richard C. | Rosenberg, Eric S. | Rosenthal, Daniel | Ross, Polly E. | Rubin, David S. | Rumbaugh, Elease | Saenz, Luis | Salvaggio, Michelle R. | Sanchez, William C. | Sanjana, Veeraf M. | Santiago, Steven | Schmidt, Wolfgang | Schuitemaker, Hanneke | Sestak, Philip M. | Shalit, Peter | Shay, William | Shirvani, Vivian N. | Silebi, Vanessa I. | Sizemore, James M. | Skolnik, Paul R. | Sokol-Anderson, Marcia | Sosman, James M. | Stabile, Paul | Stapleton, Jack T. | Starrett, Sheree | Stein, Francine | Stellbrink, Hans-Jurgen | Sterman, F. Lisa | Stone, Valerie E. | Stone, David R. | Tambussi, Giuseppe | Taplitz, Randy A. | Tedaldi, Ellen M. | Telenti, Amalio | Theisen, William | Torres, Richard | Tosiello, Lorraine | Tremblay, Cecile | Tribble, Marc A. | Trinh, Phuong D. | Tsao, Alice | Ueda, Peggy | Vaccaro, Anthony | Valadas, Emilia | Vanig, Thanes J. | Vecino, Isabel | Vega, Vilma M. | Veikley, Wenoah | Wade, Barbara H. | Walworth, Charles | Wanidworanun, Chingchai | Ward, Douglas J. | Warner, Daniel A. | Weber, Robert D. | Webster, Duncan | Weis, Steve | Wheeler, David A. | White, David J. | Wilkins, Ed | Winston, Alan | Wlodaver, Clifford G. | Wout, Angelique van’t | Wright, David P. | Yang, Otto O. | Yurdin, David L. | Zabukovic, Brandon W. | Zachary, Kimon C. | Zeeman, Beth | Zhao, Meng
Science (New York, N.Y.)  2010;330(6010):1551-1557.
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
doi:10.1126/science.1195271
PMCID: PMC3235490  PMID: 21051598
4.  Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study 
AIDS (London, England)  2010;24(17):2679-2686.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/QAD.0b013e32833f6294
PMCID: PMC3108019  PMID: 20859192
fracture; fragility fracture; HIV-infected women; premenopausal
5.  Evolution and Recombination of Genes Encoding HIV-1 Drug Resistance and Tropism during Antiretroviral Therapy 
Virology  2010;404(1):5-20.
Characterization of residual plasma virus during antiretroviral therapy (ART) is a high priority to improve understanding of HIV-1 pathogenesis and therapy. To understand the evolution of HIV-1 pol and env genes in viremic patients under selective pressure of ART, we performed longitudinal analyses of plasma-derived pol and env sequences from single HIV-1 genomes. We tested the hypotheses that drug resistance in pol was unrelated to changes in coreceptor usage (tropism), and that recombination played a role in evolution of viral strains. Recombinants were identified by using Bayesian and other computational methods. High-level genotypic resistance was seen in ~70% of X4 and R5 strains during ART. There was no significant association between resistance and tropism. Each patient displayed at least one recombinant encompassing env and representing a change in predicted tropism. These data suggest that, in addition to mutation, recombination can play a significant role in shaping HIV-1 evolution.
doi:10.1016/j.virol.2010.04.008
PMCID: PMC3186207  PMID: 20451945
HIV-1 drug resistance; HIV-1 recombination; HIV-1 tropism
6.  MICROALBUMINURIA IS ASSOCIATED WITH ALL-CAUSE AND AIDS MORTALITY IN WOMEN WITH HIV INFECTION 
Prevalence of microalbuminuria is increased in patients with HIV. Microalbuminuria is associated with increased mortality in other populations, including diabetics, for whom microalbuminuria testing is standard of care. We investigated whether microalbuminuria is associated with mortality in HIV-infected women not receiving antiretroviral therapy.
Methods
Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria were performed in specimens from two consecutive visits in 1,547 HIV-infected women enrolled in the Women’s Interagency HIV Study in 1994–1995. Time to death was modeled using proportional hazards analysis.
Results
Compared to women without albuminuria, the hazard ratio (HR) for all-cause mortality was increased in women with one (HR 3.4; 95% CI 2.2–5.2) or two specimens positive for either proteinuria or microalbuminuria (HR 3.9; 95% CI 2.1–7.0). The highest risk was observed in women with both specimens positive for proteinuria (HR 5.8; 95% CI 3.4–9.8). The association between albuminuria and all-cause mortality risk remained significant after adjustment for demographics, HIV disease severity, and related comorbidities. Similar results were obtained for AIDS death.
Conclusions
We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.
doi:10.1097/QAI.0b013e3181cc1070
PMCID: PMC2888617  PMID: 20098331
HIV; microalbuminuria; proteinuria; mortality
7.  The Effects of Opiate Use and Hepatitis C Virus Infection on Risk of Diabetes Mellitus in the Women’s Interagency HIV Study 
Background
Opiate use is common in HIV- and hepatitis C virus (HCV)-infected individuals, however its contribution to the risk of diabetes mellitus is not well understood.
Methods
Prospective study of 1,713 HIV-infected and 652 uninfected participants from the Women’s Interagency HIV Study between October 2000 and March 2006. Diabetes defined as fasting glucose ≥126 mg/dl, or self-report of diabetes medication use or confirmed diabetes diagnosis. Opiate use determined using an interviewer-administered questionnaire. Detectable plasma HCV RNA confirmed HCV infection.
Results
Current opiate users had a higher prevalence of diabetes (15%) than non-users (10%, p=.03), as well as a higher risk of incident diabetes (adjusted relative hazard [RHadj] 1.58, 95% CI 1.01, 2.46), after controlling for HCV infection, HIV/antiretroviral therapy status and diabetes risk factors including age, race/ethnicity, family history of diabetes and body mass index. HCV infection was also an independent risk factor for diabetes (RHadj 1.61, 95% CI 1.02, 2.52). HCV-infected women reporting current opiate use had the highest diabetes incidence (4.83 cases/100 person-years).
Conclusions
Among women with or at-risk for HIV, opiate use is associated with increased diabetes risk independently of HCV infection. Diabetic screening should be part of care for opiate users, and those infected with HCV.
doi:10.1097/QAI.0b013e3181d0c911
PMCID: PMC3069645  PMID: 20190642
opiate use; diabetes mellitus; fasting glucose; Hepatitis C virus; HIV; women
8.  Predictors of reported influenza vaccination in HIV-infected women in the United States, 2006-07 and 2007-08 seasons 
Preventive medicine  2010;50(5-6):223-229.
Objective
To estimate the cumulative incidence of self-reported influenza vaccination (“vaccination coverage”) and investigate predictors in HIV-infected women.
Methods
In an ongoing cohort study of HIV-infected women in five US cities, data from two influenza seasons (2006-07 n=1,209 and 2007-08 n=1,161) were used to estimate crude and adjusted prevalence ratios (aPR) and 95% confidence intervals ([,]) from Poisson regression with robust variance models using generalized estimating equations (GEE).
Results
In our study, 55% and 57% of HIV-infected women reported vaccination during the 2006-07 and 2007-08 seasons, respectively. Using data from both seasons, older age, non-smoking status, CD4 T-lymphocyte (CD4) count ≥200 cells/mm3, and reporting at least one recent healthcare visit was associated with increased vaccination coverage. In the 2007-08 season, a belief in the protection of the vaccine (aPR=1.38 [1.18, 1.61]) and influenza vaccination in the previous season (aPR=1.66 [1.44, 1.91]) most strongly predicted vaccination status.
Conclusion
Interventions to reach unvaccinated HIV-infected women should focus on changing beliefs about the effectiveness of influenza vaccination and target younger women, current smokers, those without recent healthcare visits, or a CD4 count <200 cells/mm3.
doi:10.1016/j.ypmed.2010.03.007
PMCID: PMC2883293  PMID: 20303362
HIV/AIDS; highly active antiretroviral therapy; influenza vaccine; vaccine coverage; multi-center study; cohort study; United States; adult; female
9.  Specific HLA Class I and II Alleles Associated with Hepatitis C Virus Viremia 
Hepatology (Baltimore, Md.)  2010;51(5):1514-1522.
Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multi-racial cohort of US women with high prevalence of HCV and HIV. Our primary analyses evaluated associations between twelve HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1–2.6), B*5701 (PR=2.0; 95% CI = 1.0–3.1), B*5703 (PR = 1.7; 95% CI = 1.0–2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0–3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), while DRB1*0301 (PR = 0.4; 95% CI = 0.2–0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2–11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (IDU; N=838), but no significant relationships were observed.
Conclusion
HLA genotype influences host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance since they were a priori hypothesized.
doi:10.1002/hep.23515
PMCID: PMC2946382  PMID: 20169624
human leukocyte antigen; HIV; injection drug user; multiple comparisons; killer immunoglobulin-like receptor
10.  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
11.  Time Scale and Adjusted Survival Curves for Marginal Structural Cox Models 
American Journal of Epidemiology  2010;171(6):691-700.
Typical applications of marginal structural time-to-event (e.g., Cox) models have used time on study as the time scale. Here, the authors illustrate use of time on treatment as an alternative time scale. In addition, a method is provided for estimating Kaplan-Meier–type survival curves for marginal structural models. For illustration, the authors estimate the total effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome (AIDS) or death in 1,498 US men and women infected with human immunodeficiency virus and followed for 6,556 person-years between 1995 and 2002; 323 incident cases of clinical AIDS and 59 deaths occurred. Of the remaining 1,116 participants, 77% were still under observation at the end of follow-up. By using time on study, the hazard ratio for AIDS or death comparing always with never using highly active antiretroviral therapy from the marginal structural model was 0.52 (95% confidence interval: 0.35, 0.76). By using time on treatment, the analogous hazard ratio was 0.44 (95% confidence interval: 0.32, 0.60). In time-to-event analyses, the choice of time scale may have a meaningful impact on estimates of association and precision. In the present example, use of time on treatment yielded a hazard ratio further from the null and more precise than use of time on study as the time scale.
doi:10.1093/aje/kwp418
PMCID: PMC2877453  PMID: 20139124
acquired immunodeficiency syndrome; antiretroviral therapy, highly active; bias (epidemiology); causal inference; confounding factors (epidemiology); proportional hazards model; survival curve; survival time
12.  Short term bone loss in HIV infected premenopausal women 
Background
Low bone mineral density (BMD) has been reported in HIV + women, but less is known about the longitudinal evolution of BMD and fracture incidence.
Methods
In 100 HIV+ and 68 HIV− premenopausal women in the Women’s Interagency HIV Study (WIHS), BMD was measured by dual energy x-ray absorptiometry at the femoral neck (FN) and lumbar spine (LS) at index visit and after a median of 2.5 years.
Results
In HIV+ women, BMD at index visit was normal but 5% lower at the LS and FN than in HIV− women. Annual percent decrease in BMD did not differ between HIV+ and HIV− women at the LS (−0.8±0.2% vs −0.4±0.2%, p=0.20) or FN (−0.8±0.3% vs −0.6±0.3%, p=0.56), and remained similar after adjustment for age, weight, and BMD at index visit. Among HIV+ women, bone loss was associated with vitamin D deficiency and opiate use but not with use or class of antiretrovirals. Incidence of self-reported fracture was 0.74/100 person-years in HIV+ women, and similar in HIV− women.
Conclusions
In premenopausal HIV+ women, index BMD was lower than comparable HIV− women; however, rates of bone loss at the LS and FN were similar over 2.5 years of observation, irrespective of ART.
doi:10.1097/QAI.0b013e3181bf6471
PMCID: PMC2813405  PMID: 19890216
13.  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
14.  Glycated Hemoglobin in Diabetic Women with and Without HIV Infection: Data from the Women's Interagency HIV Study 
Antiviral therapy  2010;15(4):571-577.
Background
Limited data suggest that glycated hemoglobin (hemoglobin A1c; A1C) values may not reflect glycemic control accurately in HIV-infected individuals with diabetes.
Methods
We evaluated repeated measures of paired fasting glucose and A1C values in 315 HIV-infected and 109 HIV-uninfected diabetic participants in the Women's Interagency HIV Study. Generalized estimating equations used log A1C as the outcome variable, with adjustment for log fasting glucose concentration in all models.
Results
An HIV-infected woman on average had 0.9868 times as much A1C (that is, 1.32% lower; 95% confidence interval 0.9734-0.9904) as an HIV-uninfected woman with the same log fasting glucose concentration. In multivariate analysis, HIV serostatus was not associated, but white, other non-black race, and higher red blood cell mean corpuscular volume (MCV) were statistically associated with lower A1C values. Use of diabetic medication was associated with higher A1C values. In multivariate analysis restricted to HIV-infected women, white and other race, higher MCV, and HCV viremia were associated with lower A1C values whereas older age, use of diabetic medications and higher CD4 cell count were associated with higher A1C values. Use of combination antiretroviral therapy, protease inhibitors, zidovudine, stavudine, or abacavir was not associated with A1C values.
Conclusions
We conclude that A1C values were modestly lower in HIV-infected diabetic women relative to HIV-uninfected diabetic women after adjustment for fasting glucose concentration. The difference was abrogated by adjustment for MCV, race, and diabetic medication use. Our data suggest that in clinical practice A1C gives a reasonably accurate refection of glycemic control in HIV-infected diabetic women.
doi:10.3851/IMP1557
PMCID: PMC2943237  PMID: 20587850
15.  HIV Tropism and Decreased Risk of Breast Cancer 
PLoS ONE  2010;5(12):e14349.
Background
During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.
Methods and Findings
We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load ≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.
Conclusions
Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.
doi:10.1371/journal.pone.0014349
PMCID: PMC3002931  PMID: 21179547
16.  Genital herpes evaluation by quantitative TaqMan PCR: correlating single detection and quantity of HSV-2 DNA in cervicovaginal lavage fluids with cross-sectional and longitudinal clinical data 
Virology Journal  2010;7:328.
Objective
To evaluate the utility of a single quantitative PCR (qPCR) measurement of HSV (HSV-1&2) DNA in cervicovaginal lavage (CVL) specimens collected from women with predominantly chronic HSV-2 infection in assessing genital HSV shedding and the clinical course of genital herpes (GH) within a cohort with semiannual schedule of follow up and collection of specimens.
Methods
Two previously described methods used for detection of HSV DNA in mucocutaneous swab samples were adapted for quantification of HSV DNA in CVLs. Single CVL specimens from 509 women were tested. Presence and quantity of CVL HSV DNA were explored in relation to observed cross-sectional and longitudinal clinical data.
Results
The PCR assay was sensitive and reproducible with a limit of quantification of ~50 copies per milliliter of CVL. Overall, 7% of the samples were positive for HSV-2 DNA with median log10 HSV-2 DNA copy number of 3.9 (IQR: 2.6-5.7). No HSV-1 was detected. Presence and quantity of HSV-2 DNA in CVL directly correlated with the clinical signs and symptoms of presence of active symptomatic disease with frequent recurrences.
Conclusion
Single qPCR measurement of HSV DNA in CVL fluids of women with chronic HSV-2 infection provided useful information for assessing GH in the setting of infrequent sampling of specimens. Observed positive correlation of the presence and quantity of HSV-2 DNA with the presence of active and more severe course of HSV-2 infection may have clinical significance in the evaluation and management of HSV-2 infected patients.
doi:10.1186/1743-422X-7-328
PMCID: PMC3000844  PMID: 21087488
17.  Risk Factors for Cervical Precancer and Cancer in HIV-Infected, HPV-Positive Rwandan Women 
PLoS ONE  2010;5(10):e13525.
Background
Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+).
Methods
In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women.
Results
Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm3, CI = 0.40-0.97).
Conclusions
In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women.
doi:10.1371/journal.pone.0013525
PMCID: PMC2958122  PMID: 20976000
18.  Lipoprotein levels and cardiovascular risk in HIV-infected and uninfected Rwandan women 
Background
Lipoprotein profiles in HIV-infected African women have not been well described. We assessed associations of lipoprotein levels and cardiovascular risk with HIV-infection and CD4 count in Rwandan women.
Methods
Cross-sectional study of 824 (218 HIV-negative, 606 HIV+) Rwandan women. Body composition by body impedance analysis, CD4 count, and fasting serum total cholesterol (total-C), triglycerides (TG) and high-density lipoprotein (HDL) levels were measured. Low-density lipoprotein (LDL) was calculated from Friedewald equation if TG < 400 and measured directly if TG ≥ 400 mg/dl.
Results
BMI was similar in HIV+ and -negative women, < 1% were diabetic, and HIV+ women were younger. In multivariate models LDL was not associated with HIV-serostatus. HDL was lower in HIV+ women (44 vs. 54 mg/dL, p < 0.0001) with no significant difference by CD4 count (p = 0.13). HIV serostatus (p = 0.005) and among HIV+ women lower CD4 count (p = 0.04) were associated with higher TG. BMI was independently associated with higher LDL (p = 0.01), and higher total body fat was strongly associated with higher total-C and LDL. Framingham risk scores were < 2% in both groups.
Conclusions
In this cohort of non-obese African women HDL and TG, but not LDL, were adversely associated with HIV infection. As HDL is a strong predictor of cardiovascular (CV) events in women, this HIV-associated difference may confer increased risk for CV disease in HIV-infected women.
doi:10.1186/1742-6405-7-34
PMCID: PMC2940781  PMID: 20796311
19.  Clinical Reactivations of Herpes Simplex Virus Type 2 Infection and Human Immunodeficiency Virus Disease Progression Markers 
PLoS ONE  2010;5(4):e9973.
Background
The natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear.
Methods
Clinical symptoms of active HSV-2 infection were used to classify 1,938 HIV/HSV-2 co-infected participants of the Women's Interagency HIV Study (WIHS) into groups of varying degree of HSV-2 clinical activity. Differences in plasma HIV RNA and CD4+ T cell counts between groups were explored longitudinally across three study visits and cross-sectionally at the last study visit.
Results
A dose dependent association between markers of HIV disease progression and degree of HSV-2 clinical activity was observed. In multivariate analyses after adjusting for baseline CD4+ T cell levels, active HSV-2 infection with frequent symptomatic reactivations was associated with 21% to 32% increase in the probability of detectable plasma HIV RNA (trend p = 0.004), an average of 0.27 to 0.29 log10 copies/ml higher plasma HIV RNA on a continuous scale (trend p<0.001) and 51 to 101 reduced CD4+ T cells/mm3 over time compared to asymptomatic HSV-2 infection (trend p<0.001).
Conclusions
HIV induced CD4+ T cell loss was associated with frequent symptomatic HSV-2 reactivations. However, effect of HSV-2 reactivations on HIV disease progression markers in this population was modest and appears to be dependent on the frequency and severity of reactivations. Further studies will be necessary to determine whether HSV-2 reactivations contribute to acceleration of HIV disease progression.
doi:10.1371/journal.pone.0009973
PMCID: PMC2848613  PMID: 20376310

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