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1.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
doi:10.1093/infdis/jit373
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
2.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
doi:10.1093/cid/cit003
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
3.  Missed Office Visits and Risk of Mortality Among HIV-Infected Subjects in a Large Healthcare System in the United States 
AIDS Patient Care and STDs  2013;27(8):442-449.
Abstract
Linkage and retention in care soon after HIV diagnosis improves clinical outcomes. Conversely, missed visits after diagnosis are associated with increased mortality in the public care setting. We analyzed mortality among newly diagnosed HIV patients ≥18 years old in a large private care setting between 01/01/1997 and 12/31/2009, comparing patients who missed visits in their first year following diagnosis (index period) with those who did not. Patients who died during the index period were excluded. Hazard ratios (HR) for association of missed visits and mortality were obtained by Cox proportional hazards regression, adjusting for patient demographics, CD4+ counts, and AIDS-defining conditions (CDC, 1993) at diagnosis. We also evaluated risk factors of missed visits by multivariable logistic regression. 2811 patients were included, of whom 65% had ≥1 missed visit, and 226 patients died during follow-up. Patients with ≥1 missed visit had a 71% increased mortality risk (HR=1.71, p=0.001) with 12% increased rate per missed visit (HR=1.12, p<0.001). Factors associated with missed visits were younger age (OR=1.69 compared to 60+ years), Black and Latino race/ethnicity (OR=1.54, 1.48 respectively, compared to Caucasians), injection drug use (OR=2.50 compared to men who have sex with men), and lower CD4+ (OR=1.43 for CD4+ 100–199 cells/μL, OR=1.39 for 50–99 cells/μL, and OR=1.63 for CD4+ <50 cells/μL, compared with CD4+ >500 cells/μL). In an insured patient population, missed visits in the first year of HIV care are common and associated with increased mortality. Early retention in HIV care is critical to improving outcomes.
doi:10.1089/apc.2013.0073
PMCID: PMC3739947  PMID: 23869466
4.  Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier cART will alter this risk 
Purpose of review
To critically appraise recent published literature about factors associated with cancer risk likely to be influenced by combination antiretroviral therapy (cART) in HIV-infected individuals, and the potential of earlier cART initiation to reduce this risk.
Recent findings
Factors leading to increased risk of non-AIDS defining malignancies (NADM) in particular remain poorly understood. Immunodeficiency appears to be key, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute. By reducing HIV replication, improving immune function and limiting chronic inflammation, cART initiation at higher CD4+ cell counts may therefore reduce NADM risk. However, cART only partly normalizes enhanced inflammation and coagulation seen during HIV infection and conflicting laboratory and epidemiological data have been reported as to if (and how) cART affects NADM risk. Furthermore, secondary analyses of randomized controlled trials comparing early versus delayed cART initiation were inconclusive.
Summary
Continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce cancer risk deserves further investigation.
doi:10.1097/COH.0000000000000025
PMCID: PMC3992916  PMID: 24225382
HIV; cancer; antiretroviral therapy; inflammation
5.  HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer 
Background
The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV+) individuals.
Methods
We identified 6560 HIV+ and 36 821 HIV-negative (HIV−) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV+ (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV− subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided.
Results
The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV+ and HIV− individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV+ vs HIV− subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV+ subjects compared with HIV− subjects for SCCs (P trend < .001). Adjustment for number of outpatient visits did not affect the results.
Conclusion
HIV+ subjects had a twofold higher incidence rate of NMSCs compared with HIV− subjects. SCCs but not BCCs were associated with immunodeficiency.
doi:10.1093/jnci/djs529
PMCID: PMC3589255  PMID: 23291375
6.  Strong Agreement of Nationally Recommended Retention Measures from the Institute of Medicine and Department of Health and Human Services 
PLoS ONE  2014;9(11):e111772.
Objective
We sought to quantify agreement between Institute of Medicine (IOM) and Department of Health and Human Services (DHHS) retention indicators, which have not been compared in the same population, and assess clinical retention within the largest HIV cohort collaboration in the U.S.
Design
Observational study from 2008–2010, using clinical cohort data in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
Methods
Retention definitions used HIV primary care visits. The IOM retention indicator was: ≥2 visits, ≥90 days apart, each calendar year. This was extended to a 2-year period; retention required meeting the definition in both years. The DHHS retention indicator was: ≥1 visit each semester over 2 years, each ≥60 days apart. Kappa statistics detected agreement between indicators and C statistics (areas under Receiver-Operating Characteristic curves) from logistic regression analyses summarized discrimination of the IOM indicator by the DHHS indicator.
Results
Among 36,769 patients in 2008–2009 and 34,017 in 2009–2010, there were higher percentages of participants retained in care under the IOM indicator than the DHHS indicator (80% vs. 75% in 2008–2009; 78% vs. 72% in 2009–2010, respectively) (p<0.01), persisting across all demographic and clinical characteristics (p<0.01). There was high agreement between indicators overall (κ = 0.83 in 2008–2009; κ = 0.79 in 2009–2010, p<0.001), and C statistics revealed a very strong ability to predict retention according to the IOM indicator based on DHHS indicator status, even within characteristic strata.
Conclusions
Although the IOM indicator consistently reported higher retention in care compared with the DHHS indicator, there was strong agreement between IOM and DHHS retention indicators in a cohort demographically similar to persons living with HIV/AIDS in the U.S. Persons with poorer retention represent subgroups of interest for retention improvement programs nationally, particularly in light of the White House Executive Order on the HIV Care Continuum.
doi:10.1371/journal.pone.0111772
PMCID: PMC4222946  PMID: 25375099
7.  Use of Web-based Shared Medical Records among Patients with HIV 
The American journal of managed care  2013;19(4):e114-e124.
Background
Patient websites with secure access to shared electronic medical records (SMR) may support care of patients with HIV, particularly during heightened need. However, groups disproportionately affected by HIV may be less likely to use them.
Objective & Design
We performed an observational cohort study to compare use of seven SMR features by adult patients with HIV. Automated data from the 36 months following SMR implementation were assessed in two integrated delivery systems.
Participants, Main Measures, Key Results
Most (3888/7398) patients used the SMR at least once. Users were most likely to view medical test results (49%), use secure messaging (43%), or request appointments (31%) or medication refills (30%). Initial use was associated with a new prescription for antiretroviral therapy [rate ratio (RR) 1.65, p <0.001], a recent change to CD4+ count <200 cells/μL (RR 1.34, p <0.02), a new HIV RNA ≥75 copies/mL (RR 1.63, p <0.001), or a recent increase in non-HIV comorbidity score (RR 1.49, p = 0.0001). In age-, sex-, and comorbidity-adjusted analyses, users were less likely to be women (RR 0.49, p=0.0001), injection drug users (RR 0.59, p = 0.0001), or from lower-socioeconomic neighborhoods (RR 0.68, p = 0.0001). Compared with nonusers, users were less likely to be Black (RR 0.38, p = 0.0001), Hispanic (RR 0.52, p = 0.0001) or Asian/Pacific Islander (RR 0.59, p = 0.001).
Conclusions
SMR use was higher among those with HIV who had indicators of recent increases in health care need and lower among several vulnerable populations. Health care providers and systems should support SMR use among patients with HIV as part of broader efforts to improve overall access to care.
PMCID: PMC3951974  PMID: 23725449
HIV; personal health record; health care disparities
8.  Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America 
In a large North American cohort study, anal cancer incidence rates were substantially higher for HIV-infected men who have sex with men, other men, and women compared with HIV-uninfected individuals. Rates increased from 1996–1999 to 2000–2003 but plateaued by 2004–2007.
Background. Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends.
Methods. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men).
Results. Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7–151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5–61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8–6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5–2.2). In comparison with the period 2000–2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3–.9) in 1996–1999 and 0.9 (95% CI, .6–1.2) in 2004–2007.
Conclusions. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.
doi:10.1093/cid/cir1012
PMCID: PMC3297645  PMID: 22291097
9.  Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers 
AIDS (London, England)  2013;27(9):1433-1441.
Objective
To investigate the relationship between inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)] and coagulation (D-dimer) biomarkers and cancer risk during HIV infection.
Design
A prospective cohort.
Methods
HIV-infected patients on continuous antiretroviral therapy (ART) in the control arms of three randomized trials (N = 5023) were included in an analysis of predictors of cancer (any type, infection-related or infection-unrelated). Hazard ratios for IL-6, CRP and D-dimer levels (log2-transformed) were calculated using Cox models stratified by trial and adjusted for demographics and CD4+ cell counts and adjusted also for all biomarkers simultaneously. To assess the possibility that biomarker levels were elevated at entry due to undiagnosed cancer, analyses were repeated excluding early cancer events (i.e. diagnosed during first 2 years of follow-up).
Results
During approximately 24 000 person-years of follow-up (PYFU), 172 patients developed cancer (70 infection-related; 102 infection-unrelated). The risk of developing cancer was associated with higher levels (per doubling) of IL-6 (hazard ratio 1.38, P < 0.001), CRP (hazard ratio 1.16, P = 0.001) and D-dimer (hazard ratio 1.17, P = 0.03). However, only IL-6 (hazard ratio 1.29, P = 0.003) remained associated with cancer risk when all biomarkers were considered simultaneously. Results for infection-related and infection-unrelated cancers were similar to results for any cancer. Hazard ratios excluding 69 early cancer events were 1.31 (P = 0.007), 1.14 (P = 0.02) and 1.07 (P = 0.49) for IL-6, CRP and D-dimer, respectively.
Conclusion
Activated inflammation and coagulation pathways are associated with increased cancer risk during HIV infection. This association was stronger for IL-6 and persisted after excluding early cancer. Trials of interventions may be warranted to assess whether cancer risk can be reduced by lowering IL-6 levels in HIV-positive individuals.
doi:10.1097/QAD.0b013e32835f6b0c
PMCID: PMC4046103  PMID: 23945504
biomarkers; cancer; C-reactive protein; D-dimer; HIV; interleukin-6
10.  PRESCRIPTION LONG-TERM OPIOID USE IN HIV-INFECTED PATIENTS 
The Clinical journal of pain  2012;28(1):39-46.
Objectives
To examine changes in use of prescription opioids for the management of chronic non-cancer pain in HIV-infected patients and to identify patient characteristics associated with long-term use.
Methods
Long-term prescription opioid use (i.e. 120+ days supply or 10+ prescriptions during a year) was assessed between 1997 and 2005 among 6,939 HIV-infected Kaiser Permanente members and HIV-uninfected persons in the general health plan memberships.
Results
In 2005, 8% of HIV+ individuals had prevalent long-term opioid use, more than double the prevalence among HIV-uninfected individuals. However, the large increases in use from 1997 to 2005 in the general population were not observed for HIV-infected individuals. The strongest associations with prevalent use among HIV-infected individuals were female gender with a prevalence ratio [PR] of 1.8 (95% CI=1.3, 2.5); Charlson comorbidity score of 2 or more (compared with a score of 0) with a PR of 1.9 (95% CI=1.4, 2.8); injection drug use history with a PR of 1.8 (95% CI=1.3, 2.6); substance use disorders with a PR of 1.8 (95% CI=1.3, 2.5). CD4, HIV RNA, and AIDS diagnoses were associated with prevalent opioid use early in the antiretroviral therapy era (1997), but not in 2005.
Conclusions
Long-term opioid use for chronic pain has remained stable over time for HIV patients, while use increased in the general population. The prevalence of prescribed opioids in HIV patients was highest for certain subgroups, including women, and those with a comorbidity and substance abuse history.
doi:10.1097/AJP.0b013e3182201a0f
PMCID: PMC3175344  PMID: 21677568
HIV/AIDS; chronic pain; prescription opioids; substance use disorders
11.  HIV infection, Immunodeficiency, Viral Replication and the Risk of Cancer 
Background
Few studies have compared cancer risk between HIV-infected individuals and a demographically-similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.
Methods
We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996–2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity.
Results
We observed elevated RRs for Kaposi sarcoma (KS) (RR=199; P<0.001), non-Hodgkin lymphoma (NHL) (RR=15; P<0.001), anal cancer (RR=55; P<0.001), Hodgkin lymphoma (HL) (RR=19; P<0.001), melanoma (RR=1.8; P=0.001), and liver cancer (RR=1.8; P=0.013), a reduced RR for prostate cancer (RR=0.8; P=0.012), and no increased risk for oral cavity/pharynx (RR=1.4; P=0.14), lung (RR=1.2; P=0.15), or colorectal (RR=0.9; P=0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P<0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 <200 cells/µL and for melanoma and liver cancer with CD4 <500 cells/µL. Only KS and NHL were associated with HIV RNA.
Conclusion
Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors.
Impact
Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population.
doi:10.1158/1055-9965.EPI-11-0777
PMCID: PMC3237725  PMID: 22109347
HIV/AIDS; cancer; immunodeficiency; viral replication; epidemiology
12.  Retention Among North American HIV–infected Persons in Clinical Care, 2000–2008 
Background
Retention in care is key to improving HIV outcomes. Our goal was to describe “churn” in patterns of entry, exit, and retention in HIV care in the US and Canada.
Methods
Adults contributing ≥1 CD4 count or HIV-1 RNA (HIV-lab) from 2000–2008 in North American Cohort Collaboration on Research and Design (NA-ACCORD) clinical cohorts were included. Incomplete retention was defined as lack of 2 HIV-labs (≥90 days apart) within 12 months, summarized by calendar year. We used beta-binomial regression models to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) of factors associated with incomplete retention.
Results
Among 61,438 participants, 15,360 (25%) with incomplete retention significantly differed in univariate analyses (p<0.001) from 46,078 (75%) consistently retained by age, race/ethnicity, HIV risk, CD4, ART use, and country of care (US vs. Canada). From 2000–2004, females (OR=0.82, CI:0.70–0.95), older individuals (OR=0.78, CI:0.74–0.83 per 10 years), and ART users (OR= 0.61, CI:0.54–0.68 vs all others) were less likely to have incomplete retention, while black individuals (OR=1.31, CI:1.16–1.49, vs. white), those with injection drug use (IDU) HIV risk (OR=1.68, CI:1.49–1.89, vs. non-IDU) and those in care longer (OR=1.09, CI:1.07–1.11 per year) were more likely to have incomplete retention. Results from 2005–2008 were similar.
Discussion
From 2000 to 2008, 75% of the NA-ACCORD population was consistently retained in care with 25% experiencing some change in status, or churn. In addition to the programmatic and policy implications, our findings identify patient groups who may benefit from focused retention efforts.
doi:10.1097/QAI.0b013e31827f578a
PMCID: PMC3661708  PMID: 23242158
retention; churn; HIV clinical care; North America; HRSA HAB; National HIV/AIDS Strategy
13.  Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada 
PLoS ONE  2013;8(12):e81355.
Background
Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada.
Methods
Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables.
Results
The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000–2002 to 2006–2007. Men and women had comparable life expectancies in all periods except the last (2006–2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm3.
Conclusions
A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.
doi:10.1371/journal.pone.0081355
PMCID: PMC3867319  PMID: 24367482
14.  Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma 
Background
Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL), and examined the prognostic utility of detecting EBV infection.
Study Design
HIV-related DLBCL cases diagnosed between 1996–2007 within Kaiser Permanente California were identified. Immunohistochemistry staining was used to analyze the expression of selected markers that are cell cycle regulators, B-cell activators, and anti-apoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman’s correlation coefficient. The prognostic utility of EBV status was examined in multivariable Cox model adjusting for international prognostic index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination.
Results
Seventy HIV-related DLBCL cases were included (31% EBV+). EBV+ tumor was associated with increased expression of BLIMP1 and CD30, and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [hazard ratio=3.3 (95% CI: 1.6–6.6)]. Area under the ROC curve demonstrated improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)].
Conclusion
Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-κB pathway, and that detecting tumor EBV status may have prognostic utility in HIV-related DLBCL.
doi:10.1158/1078-0432.CCR-11-3169
PMCID: PMC3846529  PMID: 22711707
EBV; Lymphoma; HIV; Diffuse large B-cell lymphoma; Prognosis
15.  HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons 
AIDS (London, England)  2011;25(14):10.1097/QAD.0b013e328349c67a.
Objective
Experimental studies suggested that HMG-CoA reductase inhibitors (‘statins’) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons.
Design
A nested case–control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization.
Methods
Cases were incident HIV+NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente’s electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV+NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT).
Results
A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV+NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31–0.95), 0.64 (0.31–1.28), and 0.50 (0.23–1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed.
Conclusion
Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.
doi:10.1097/QAD.0b013e328349c67a
PMCID: PMC3846691  PMID: 21681055
AIDS; HIV; HMG-CoA reductase; inhibitors; lymphoma; non-Hodgkin lymphoma; statins
16.  Risk Factors for Short-Term Virologic Outcomes Among HIV-Infected Patients Undergoing Regimen Switch of Combination Antiretroviral Therapy 
AIDS Research and Human Retroviruses  2012;28(12):1630-1636.
Abstract
We investigated risk factors for unfavorable virologic responses among HIV-infected patients who recently switched antiretroviral regimens. We identified HIV-infected patients who switched antiretroviral regimens (defined as adding ≥2 new medications) between 2001 and 2008 at Kaiser Permanente California. Virological response, measured after 6 months on the new regimen, was classified as (1) maximal viral suppression (HIV RNA <75/ml), (2) low-level viremia (LLV; 75–5000/ml), or (3) advanced virologic failure (>5000/ml). Potential risk factors examined included (1) HIV disease factors, e.g., prior AIDS, CD4 cell count; (2) history of antiretroviral use, e.g., therapy classes of the newly switched regimen, medication adherence, and virologic failure at previous regimens; and (3) novel patient-level factors including comorbidities and healthcare utilization. Adjusted odds ratios (aOR) for LLV and advanced virologic failure were obtained from multivariable nominal logistic regression models. A total of 3447 patients were included; 2608 (76%) achieved maximal viral suppression, 420 (12%) had LLV, and 419 (12%) developed advanced virologic failure. Factors positively associated with LLV and advanced virologic failure included number of regimens prior to switch [aORper regimen=1.38 (1.17–1.62) and 1.77 (1.50–2.08), respectively], nucleotide reverse transcriptase inhibitor-only regimens (vs. protease inhibitor-based) [aOR=2.78 (1.28–6.04) and 5.10 (2.38–10.90), respectively], and virologic failure at previous regimens [aOR=3.15 (2.17–4.57) and 4.71 (2.84–7.81), respectively]. Older age, higher CD4 cell count, and medication adherence were protective for unfavorable virologic outcomes. Antiretroviral regimen-level factors and immunodeficiency were significantly associated with virologic failure after a recent therapy switch and should be considered when making treatment change decisions.
doi:10.1089/aid.2012.0005
PMCID: PMC3505044  PMID: 22475276
17.  Association between U.S. State AIDS Drug Assistance Program (ADAP) Features and HIV Antiretroviral Therapy Initiation, 2001–2009 
PLoS ONE  2013;8(11):e78952.
Background
U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes.
Methods
We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU).
Results
Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60–0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87–1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47–0.95).
Conclusions
We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.
doi:10.1371/journal.pone.0078952
PMCID: PMC3832515  PMID: 24260137
18.  Age and Racial / Ethnic Differences in the Prevalence of Reported Symptoms in HIV-Infected Persons on Antiretroviral Therapy 
Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in HIV infection. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1,574 HIV-infected women enrolled in the Women’s Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly-active antiretroviral therapy. It was observed that women ≥50 years were less likely to experience gastrointestinal symptoms (24% vs. 27%, multivariable p=0.024), but more likely to experience general malaise (47% vs. 37%; multivariable p=0.004), neurologic (44% vs. 38%; multivariable p=0.048), or other symptoms (40% vs. 28%; multivariable P<0.001) compared to women <40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P=0.002), largely driven by paresthesias (48% vs. 31%; multivariable p=0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms and African-American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of AIDS were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.
doi:10.1016/j.jpainsymman.2008.08.007
PMCID: PMC2858004  PMID: 19329274
Highly active antiretroviral therapy; symptoms; gender; race/ethnicity; aging
19.  HIV infection, aging, and immune function: implications for cancer risk and prevention 
Current opinion in oncology  2012;24(5):506-516.
Purpose of review
Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions.
Recent findings
There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood.
Summary
Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.
doi:10.1097/CCO.0b013e328355e131
PMCID: PMC3695478  PMID: 22759737
aging; cancer; HIV; immune system; inflammation
20.  DO ANTIRETROVIRALS REDUCE THE RISK OF NON-AIDS DEFINING MALIGNANCIES? 
Purpose of review
There is an increasing burden of non-AIDS-defining malignancies (NADM) in the antiretroviral therapy (ART) era. The recent literature is reviewed with respect to NADM risk, ART use, and immune function.
Recent findings
Recent studies have increasingly focused on individual ART use, CD4 T-cell counts and the risk of NADMs. Certain NADMs have been shown to have a reduced risk with ART use including liver, breast, colorectal, and lung cancers. NADMs associated with immunosuppression included Hodgkin’s lymphoma, oral/pharynx, lung, anal, and colorectal cancers. Despite the potential protective effect of ART on some NADMs, recent studies evaluating calendar era trends have noted an increased risk of Hodgkin’s lymphoma and anal cancer, and no change in risk for lung cancer in the ART era.
Summary
Successful ART use and improvements in immune function for HIV-infected persons may reduce the risk of certain NADMs. However, a continued high risk in the ART era for certain cancers have been observed, including Hodgkin’s lymphoma and anal cancers. Future studies should monitor trends in NADMs in HIV-infected persons in the ART era, as well as changes in the prevalence of risk factors, co-infections, and screening practices in this population.
doi:10.1097/COH.0b013e32831a9875
PMCID: PMC2698664  PMID: 19339938
HIV; antiretroviral therapy; immunodeficiency; malignancy
22.  The Effect of HIV Infection, Immunodeficiency and Antiretroviral Therapy on the Risk of Hepatic Dysfunction 
Background
Limited data exists regarding the effect of chronic HIV infection on the liver. We sought to characterize the hepatic risks of HIV infection, immunodeficiency and cumulative use of antiretroviral therapy (ART).
Methods
Adult HIV-infected and 10:1 age- and sex-matched HIV-uninfected individuals were followed for incident hepatic dysfunction or hepatic dysfunction-related death. Multivariable Poisson regression models were used to obtain incident rate ratios, adjusting for multiple hepatic risk factors including alcohol/drug abuse, hepatitis B and C, and diabetes.
Results
We identified 20,775 HIV-infected and 215,158 HIV-uninfected individuals. HIV-infected individuals had a significantly greater overall risk compared with HIV-uninfected individuals of both hepatic dysfunction and hepatic dysfunction-related death. The highest risk was seen in patients with low CD4 cell counts not on ART (adjusted rate ratio (aRR) of hepatic dysfunction-related death 59.4; (95% confidence interval [CI]: 39.3–89.7), P< 0.001; hepatic dysfunction, aRR 15.7 (95% CI: 11.4–21.6), P<0.001. In an HIV-infected only model, factors that increased risk included low CD4 cell count, high HIV RNA level, alcohol/drug abuse, hepatitis B or C co-infection, and diabetes. Longer cumulative exposure to ART did not increase risk, regardless of therapy class.
Conclusions
HIV-infected individuals have a higher risk of hepatic dysfunction and hepatic dysfunction-related death compared with HIV-uninfected individuals, even with adjustment for known hepatic risk factors. Hepatic outcomes were associated with lower CD4+ T-cell counts, but not with longer cumulative ART exposure. These findings provide indirect evidence supporting early use of ART to reduce the risk for hepatic-related complications.
doi:10.1097/QAI.0b013e31824e9ef2
PMCID: PMC3376230  PMID: 22343179
Hepatic Dysfunction; Hepatic Failure; Liver Failure; Hepatic Dysfunction-Related Death; HIV Infection; Antiretroviral Therapy
24.  Prevalence of Clinical Symptoms Associated with Highly Active Antiretroviral Therapy in the Women’s Interagency HIV Study 
Background
The extended use of antiretroviral drugs among human immunodeficiency virus (HIV)–seropositive individuals underscores the need for a comprehensive evaluation of therapy-associated clinical symptoms.
Methods
Beginning in April 2000, 364 HIV-seronegative and 1256 HIV-seropositive women enrolled in a multicenter cohort study reported clinical symptoms that included abdominal pain, diarrhea, anorexia, nausea and/or vomiting, myalgias, fatigue, fever, body fat redistribution, dizziness, headaches, paresthesias, xerostomia, nephrolithiasis, and rash. We examined the prevalence of symptoms with respect to HIV infection and the use of highly active antiretroviral therapy (HAART), using data-correlation models.
Results
In the 6 months before a study visit, 49% of HIV-seronegative women, 67% of HIV-seropositive women not receiving therapy, and 69% of HIV-seropositive women receiving HAART reported any clinical symptom. The odds ratios (ORs) for reporting any symptom were 1.4 (95% confidence interval [CI], 1.1–1.8) for women who changed HAART regimens and 0.9 (95% CI, 0.7–1.1) for women reporting stable HAART use, compared with those reporting no therapy use. Significant findings (P < .05) for particular symptoms were an increased odds of diarrhea, nausea and/or vomiting, body fat redistribution, myalgias, and paresthesias, when data for women who changed HAART regimens were compared with those for women not receiving therapy. The OR for reporting any symptom was 1.5 (95% CI, 1.2–1.9) for women who switched HAART regimens and 1.6 (95% CI, 1.3–1.9) for women who discontinued HAART, compared with those reporting stable HAART use.
Conclusions
Our findings confirm the high prevalence of clinical symptoms among HIV-seropositive women who changed HAART regimens. The high prevalence of symptoms among HIV-seronegative women and HIV-seropositive women not receiving therapy demonstrates that caution should be used when attributing the occurrence of symptoms entirely to HAART.
doi:10.1086/423181
PMCID: PMC3118991  PMID: 15356788
25.  CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection 
AIDS (London, England)  2008;22(7):841-848.
Background
Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients.
Objective
To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy.
Methods
CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations.
Results
A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/μl; 2.0 and 1.7 for counts of 200–350 cells/μl; and 0.7 and 0.7 for counts greater than 350 cells/μl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50–0.62, P <0.01) and 14% (95% confidence interval for hazard ratio 0.77–0.96, P =0.01), respectively, for each 100 cell/μl higher latest CD4+ count.
Conclusion
Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/μl.
doi:10.1097/QAD.0b013e3282f7cb76
PMCID: PMC3618460  PMID: 18427202
AIDS; antiretroviral therapy; CD4 count; HIV morbidity and mortality; non-AIDS conditions

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