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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.
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.
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
3.  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.
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.
Observational study from 2008–2010, using clinical cohort data in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
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.
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.
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.
PMCID: PMC4222946  PMID: 25375099
4.  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.
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.
PMCID: PMC3739947  PMID: 23869466
5.  Comparative Health Systems Research among Kaiser Permanente and Other Integrated Delivery Systems: A Systematic Literature Review 
The Permanente Journal  2014;18(3):66-77.
Because of rising health care costs, wide variations in quality, and increased patient complexity, the US health care system is undergoing rapid changes that include payment reform and movement toward integrated delivery systems. Well-established integrated delivery systems, such as Kaiser Permanente (KP), should work to identify the specific system-level factors that result in superior patient outcomes in response to policymakers’ concerns. Comparative health systems research can provide insights into which particular aspects of the integrated delivery system result in improved care delivery.
To provide a baseline understanding of comparative health systems research related to integrated delivery systems and KP.
Systematic literature review.
We conducted a literature search on PubMed and the KP Publications Library. Studies that compared KP as a system or organization with other health care systems or across KP facilities internally were included. The literature search identified 1605 articles, of which 65 met the study inclusion criteria and were examined by 3 reviewers.
Most comparative health systems studies focused on intra-KP comparisons (n = 42). Fewer studies compared KP with other US (n = 15) or international (n = 12) health care systems. Several themes emerged from the literature as possible factors that may contribute to improved care delivery in integrated delivery systems.
Of all studies published by or about KP, only a small proportion of articles (4%) was identified as being comparative health systems research. Additional empirical studies that compare the specific factors of the integrated delivery system model with other systems of care are needed to better understand the “system-level” factors that result in improved and/or diminished care delivery.
PMCID: PMC4116268  PMID: 24937150
6.  Cost of Care for HIV-Infected Patients with Co-Occurring Substance Use Disorder or Psychiatric Disease: Report from a Large, Integrated Health Plan 
AIDS Research and Treatment  2014;2014:570546.
Background. The costs of providing care to HIV-infected (HIV+) patients with co-occurring diagnoses of substance use (SU) disorder or psychiatric disease (PD) are not well documented. It is our objective to evaluate costs in these HIV+ patients receiving care in a large health plan. Methods. We conducted a retrospective cohort study from 1995 to 2010 to compare costs of healthcare in HIV+ patients with and without co-occurring SU disorder and/or PD diagnoses. Estimates of proportional differences in costs (rate ratios) were obtained from repeated measures generalized linear regression. Models were stratified by cost category (e.g., inpatient, outpatient). Results. Mean total healthcare costs per patient per year were higher in HIV+ patients diagnosed with SU disorder or PD compared to HIV+ patients without these comorbid conditions. After controlling for confounders, total mean costs remained significantly higher in patients diagnosed with SU disorder (RR = 1.24, 95% CI = 1.18–1.31) or PD (RR = 1.19, 95% CI = 1.15–1.24). Mean outpatient care costs were significantly greater in patients with both SU disorder and PD (RR = 1.52, 95% CI = 1.41–1.64). Conclusions. Given these higher expenditures in the care of HIV+ patients with comorbid SU disorder and/or PD, greater efforts to facilitate SU disorder or PD treatment initiation and persistence could provide substantial savings.
PMCID: PMC4090559  PMID: 25045533
7.  Use of Web-based Shared Medical Records among Patients with HIV 
The American journal of managed care  2013;19(4):e114-e124.
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).
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.  Retention Among North American HIV–infected Persons in Clinical Care, 2000–2008 
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.
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.
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.
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.
PMCID: PMC3661708  PMID: 23242158
retention; churn; HIV clinical care; North America; HRSA HAB; National HIV/AIDS Strategy
9.  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.
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.
A nested case–control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization.
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).
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.
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.
PMCID: PMC3846691  PMID: 21681055
AIDS; HIV; HMG-CoA reductase; inhibitors; lymphoma; non-Hodgkin lymphoma; statins
10.  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.
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.
PMCID: PMC3505044  PMID: 22475276
11.  Association between U.S. State AIDS Drug Assistance Program (ADAP) Features and HIV Antiretroviral Therapy Initiation, 2001–2009 
PLoS ONE  2013;8(11):e78952.
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.
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).
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).
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.
PMCID: PMC3832515  PMID: 24260137
12.  The Effect of HIV Infection, Immunodeficiency and Antiretroviral Therapy on the Risk of Hepatic Dysfunction 
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).
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.
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.
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.
PMCID: PMC3376230  PMID: 22343179
Hepatic Dysfunction; Hepatic Failure; Liver Failure; Hepatic Dysfunction-Related Death; HIV Infection; Antiretroviral Therapy
13.  Determination of Optimized Multidisciplinary Care Team for Maximal Antiretroviral Therapy Adherence 
We seek to determine the optimized multidisciplinary care team (MDCT) composition for antiretroviral therapy (ART) adherence.
We analyzed all new regimen starts (n=10,801; 7,071 ART naïve, 3,730 ART experienced) among HIV+ patients in Kaiser Permanente California from 1996–2006. We measured 12-month adherence to ART (pharmacy refill methodology) and medical center-specific patient exposure to HIV/ID specialist (reference group), non-HIV primary care provider (PC), clinical pharmacist, nurse case manager, non-nurse care coordinator, dietician, social worker/benefits coordinator, health educator, and mental health. We used recursive partitioning to ascertain potential MDCT compositions associated with maximal mean ART adherence. We then employed mixed linear regression with clustering by provider and medical center (adjusting for ART experience, age, gender, race/ethnicity, HIV risk, HCV+, ART regimen class and calendar year) to test which potential MDCT identified had statistically significant association with ART adherence.
We found maximal increase in adherence with pharmacist +coordinator +PC (+8.1% ART adherence difference compared to reference; 95%CI: +2.7–+13.5%). Other MDCT teams with significant (p<0.05) improved adherence compared to specialist only were: nurse +social work +PC (+7.5%; +5.4–+9.7%); specialist +mental health (+6.5%; +2.6–+10.4%); pharmacist +social work +PC (+5.7%; +4.1–+7.4%); pharmacist +PC (+3.3%; +0.8–+5.8%). Among these MDCTs, there were no significant differences in mean adherence, odds maximal viral control, or change CD4+ at 12 months (except pharmacist +PC).
Various MDCTs were associated with improved adherence, including ones that did not include HIV specialist but included primary care plus other health professionals. These findings have application to HIV care team design.
PMCID: PMC3360831  PMID: 22293551
Multidisciplinary Care Team; Antiretroviral Therapy Adherence; Clinical Pharmacist; Patient Centered Medical Home; HIV Specialist; Recursive Partitioning
15.  HIV Status is An Independent Risk Factor for Reporting Lower Urinary Tract Symptoms 
The Journal of urology  2011;185(5):1710-1715.
HIV/AIDS is a worldwide epidemic. Limited evidence suggests that men infected with HIV/AIDS are at increased risk for lower urinary tract symptoms. We determined whether HIV/AIDS status is an independent risk factor for self-reported bothersome lower urinary tract symptoms in a large contemporary cohort.
Materials and Methods
We performed a cross-sectional, Internet based survey of urinary quality of life outcomes in adult HIV infected and HIV uninfected men who have sex with men. The main outcome measure was International Prostate Symptom Score.
Of respondents with complete data 1,507 were HIV uninfected (median age 42 years, mean 43) and 323 HIV infected (median age 45 years, mean 45.1). Of the HIV infected respondents 148 were nonAIDS defining HIV infected and 175 were AIDS defining HIV infected. After adjusting for age and other comorbid conditions, nonAIDS defining HIV infected and AIDS defining HIV infected status increased the odds of severe lower urinary tract symptoms by 2.07 (95% CI 1.04–3.79) and 2.49 (95% CI 1.43–4.33), respectively. HIV infected men had a worse total International Prostate Symptom Score for all domains including quality of life compared to HIV uninfected men. Within the population of men with HIV, those with AIDS had worse mean total International Prostate Symptom Score and all individual International Prostate Symptom Score components relative to nonAIDS defining HIV infected men.
HIV status is an independent risk factor for bothersome lower urinary tract symptoms. The odds of severe lower urinary tract symptoms are greater in HIV infected men with a history of AIDS.
PMCID: PMC3565615  PMID: 21420120
urinary tract; signs and symptoms; HIV
16.  Provision of Contraceptive Services to Women with Diabetes Mellitus 
Women with diabetes mellitus who delay pregnancy until glycemic control is achieved experience lower rates of adverse pregnancy outcomes.
To compare rates of provision of contraceptive services among women with diabetes mellitus and women without chronic medical conditions.
A retrospective cohort study of 459,181 women aged 15–44 who had continuous membership and pharmacy benefits in a managed care organization in Northern California between January 2006 and June 2007. Rates of documented provision of contraceptive counseling, prescriptions, and services were compared between women with diabetes and women without chronic medical conditions.
Among 8,182 women with diabetes and 122,921 women without any chronic conditions, women with diabetes were less likely than women without a chronic condition to have documented receipt of any contraceptive counseling, prescriptions, or services (47.8% vs 62.0%, p < 0.001). After controlling for age and race, women with diabetes were more likely to have undergone tubal sterilization compared to women without a chronic condition (OR = 1.41, 95% CI 1.30–1.54), but less likely to have received highly effective, reversible methods of contraception such as intrauterine contraception (OR = 0.68, 95% CI 0.61–0.75). In addition, more women with diabetes had undergone hysterectomy, which is rarely performed solely for contraceptive purposes.
Women with diabetes were less likely to receive highly effective reversible contraception and more likely to undergo sterilization procedures. Increasing the use of highly effective reversible contraceptives may help diabetic women who want to retain their fertility to delay pregnancy until glycemic control is achieved.
PMCID: PMC3270235  PMID: 21922154
diabetes mellitus; pregnancy; contraception; preconception counseling; women
17.  U.S. Trends in Antiretroviral Therapy Use, HIV RNA Plasma Viral Loads, and CD4 T-Lymphocyte Cell Counts Among HIV-Infected Persons, 2000 to 2008 
Annals of internal medicine  2012;157(5):325-335.
The U.S. National HIV/AIDS Strategy targets for 2015 include increasing access to care and improving health outcomes for persons living with HIV in the United States (PLWH-US).
To demonstrate the utility of the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) for monitoring trends in the HIV epidemic in the United States and to present trends in HIV treatment and related health outcomes.
Trends from annual cross-sectional analyses comparing patients from pooled, multicenter, prospective, clinical HIV cohort studies with PLWH-US, as reported to national surveillance systems in 40 states.
U.S. HIV outpatient clinics.
HIV-infected adults with 1 or more HIV RNA plasma viral load (HIV VL) or CD4 T-lymphocyte (CD4) cell count measured in any calendar year from 1 January 2000 to 31 December 2008.
Annual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death.
45 529 HIV-infected persons received care in an NA-ACCORD–participating U.S. clinical cohort from 2000 to 2008. In 2008, the 26 030 NA-ACCORD participants in care and the 655 966 PLWH-US had qualitatively similar demographic characteristics. From 2000 to 2008, the proportion of participants prescribed highly active antiretroviral therapy increased by 9 percentage points to 83% (P < 0.001), whereas the proportion with suppressed HIV VL (≤2.7 log10 copies/mL) increased by 26 percentage points to 72% (P < 0.001). Median CD4 cell count at death more than tripled to 0.209 × 109 cells/L (P < 0.001).
The usual limitations of observational data apply.
The NA-ACCORD is the largest cohort of HIV-infected adults in clinical care in the United States that is demographically similar to PLWH-US in 2008. From 2000 to 2008, increases were observed in the percentage of prescribed HAART, the percentage who achieved a suppressed HIV VL, and the median CD4 cell count at death.
Primary Funding Source
National Institutes of Health, Centers for Disease Control and Prevention, Canadian Institutes of Health Research, Canadian HIV Trials Network, and the government of British Columbia, Canada.
PMCID: PMC3534765  PMID: 22944874
18.  Essential Components of Effective HIV Care: A Policy Paper of the HIV Medicine Association of the Infectious Diseases Society of America and the Ryan White Medical Providers Coalition 
Human immunodeficiency virus (HIV) antiretroviral agents and effective HIV care management transformed HIV disease from a death sentence to a chronic condition for many in the United States. A comprehensive HIV care model was developed to meet the complex needs of HIV patients, with support from the Ryan White program, the Veterans Administration, and others. This paper identifies the essential components of an effective HIV care model. As access to health care expands under the National HIV/AIDS Strategy and the Patient Protection and Affordable Care Act, it will be critical to build upon the HIV care model to realize positive health outcomes for people with HIV infection.
PMCID: PMC3205204  PMID: 22021928
19.  HIV infection, Immunodeficiency, Viral Replication and the Risk of Cancer 
Few studies have compared cancer risk between HIV-infected individuals and a demographically-similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.
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.
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.
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.
Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population.
PMCID: PMC3237725  PMID: 22109347
HIV/AIDS; cancer; immunodeficiency; viral replication; epidemiology
20.  Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening 
The Journal of Infectious Diseases  2011;204(6):893-901.
Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts.
Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence.
Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk.
Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
PMCID: PMC3156918  PMID: 21849286
21.  Missing Data on the Estimation of the Prevalence of Accumulated Human Immunodeficiency Virus Drug Resistance in Patients Treated With Antiretroviral Drugs in North America 
American Journal of Epidemiology  2011;174(6):727-735.
Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic-based cohorts from the North American AIDS Cohort Collaboration on Research and Design, drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005, the prevalence was calculated using data from the tested subset, assumptions that incorporated clinical knowledge, and multiple imputation methods to yield a complete data set. A total of 9,289 patients contributed data to the analysis; 3,959 had at least 1 viral load above 1,000 copies/mL, of whom 2,962 (75%) had undergone at least 1 genotype test. Using these methods, the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast, the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors’ use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests.
PMCID: PMC3202147  PMID: 21813792
antiretroviral therapy, highly active; drug resistance; genotype; HIV
22.  Influence of provider experience on antiretroviral adherence and viral suppression 
HIV/AIDS (Auckland, N.Z.)  2012;4:125-133.
Background and aim
Early in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience.
We performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naïve, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996–2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0–10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty ( noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year.
Among the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2–5 years experience; 3.7% 5–10 years; 2.7% 11–20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naïve was positively associated with panel size (odds ratio 26–50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naïve or odds of maximal viral suppression among ART-experienced in adjusted analysis.
Except for panel size and years experience among ART-naïve, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.
PMCID: PMC3423649  PMID: 22924015
antiretroviral therapy; adherence; provider-level factors; HIV-related outcomes
23.  Sexual Dysfunction, HIV, and AIDS in Men Who Have Sex with Men 
AIDS Patient Care and STDs  2011;25(6):341-349.
HIV infection is associated with sexual dysfunction. Using validated instruments, we investigated the relationship between HIV/AIDS and sexual function in a contemporary cohort of men who have sex with men (MSM). An anonymous Internet-based survey was disseminated to MSM via organizations and social networking sites that cater to this population. Information on ethnodemographic variables, health status (including HIV status, disease stage, and other health conditions), and sexual behavior was collected. Men were categorized as HIV-negative, HIV-positive/AIDS-negative, or HIV-positive /AIDS-positive. A modified validated version of the International Index of Erectile Function (IIEF) for use in MSM and the Premature Ejaculation Diagnostic Tool (PEDT) were used to stratify risk of sexual dysfunction. The study cohort included 1361 men (236 of whom were HIV-positive) who provided complete data on HIV status, IIEF, and PEDT. There was a significant trend toward greater prevalence of erectile dysfunction (ED) in men with progressive HIV infection 40–59 years of age relative to age matched HIV-negative men (p=0.02). In a logistic regression model controlling for other variables, HIV infection without AIDS was not associated with greater odds of ED; however, HIV infection with AIDS was associated with greater odds of ED (p=0.006). In a separate logistic regression model, HIV infection with or without AIDS was not significantly associated with greater odds of premature ejaculation (p>0.05). Use of phosphodiesterase 5 (PDE5) inhibitor drugs was much more common in HIV-infected men. HIV infection is a risk factor for poorer sexual function primarily due to higher risk of erectile dysfunction in men with AIDS.
PMCID: PMC3101920  PMID: 21501095
24.  Survival of Non-Hodgkin Lymphoma Patients with and without HIV-Infection in the Era of Combined Antiretroviral Therapy 
AIDS (London, England)  2010;24(11):1765-1770.
To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. -uninfected patients from the same integrated health care system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy (cART).
Cohort study.
Incident NHL diagnosed between 1996–2005 were identified from members of Kaiser Permanente (KP) California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma- and HIV-related characteristics for the same outcomes were also examined.
A total of 259 HIV-infected and 8,230 HIV-uninfected incident NHL cases were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis, compared to 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (Relative Risk=2.0, 95% Confidence Interval=1.7–2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages and histologic subtypes. HIV-infected patients with CD4 cell count <200/mm3 and/or prior AIDS-defining illness were also at increased risk for lymphoma-specific mortality compared to HIV-uninfected patients. Among HIV-infected NHL cases, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt’s subtype.
HIV-infected patients with NHL in the cART era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.
PMCID: PMC2895006  PMID: 20453630
HIV infection; non-Hodgkin lymphoma; prognostic factors; antiretroviral therapy; mortality
25.  Late Presentation for HIV Care in the United States and Canada 
Initiatives to improve early detection and access to HIV services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997-2007 in 13 US and Canadian clinical cohorts.
We analyzed data from 44,491 HIV-infected patients enrolled in the North American – AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4+ T-lymphocyte (CD4) measurement and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm3) and 95% confidence intervals ([,]) were determined using linear regression adjusted for age, gender, race/ethnicity, HIV transmission risk and cohort.
Median age at first presentation for HIV care increased over time (range 40-43 years, p<0.01), while the proportion of patients with injection drug use HIV transmission risk decreased (26% to 14%, p<0.01) and heterosexual transmission risk increased (16% to 23%, p<0.01). Median CD4 at presentation increased from 256 (IQR: 96-455) to 317 (IQR: 135-517) in 1997 to 2007 (p<0.01). The proportion with a CD4 count ≥350 at first presentation also increased from 1997 to 2007 (38% to 46%, p=<0.01). The estimated adjusted mean CD4 count increased at a rate of 6 [5, 7] per year.
CD4 count at first presentation for HIV care has increased annually over the past 11 years, but has remained <350 cells/mm3, suggesting the urgent need for earlier HIV diagnosis and treatment.
PMCID: PMC2862849  PMID: 20415573
CD4 Lymphocyte Count; Delivery of Health Care / statistics & numerical data; HIV Infections / therapy; United States; Canada

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