Disparities in achieving and sustaining viral suppression among a large cohort of HIV-infected persons in care - Washington, DC.

One goal of the HIV care continuum is achieving viral suppression (VS), yet disparities in suppression exist among subpopulations of HIV-infected persons. We sought to identify disparities in both the ability to achieve and sustain VS among an urban cohort of HIV-infected persons in care. Data from HIV-infected persons enrolled at the 13 DC Cohort study clinical sites between January 2011 and June 2014 were analyzed. Univariate and multivariate logistic regression were conducted to identify factors associated with achieving VS (viral load < 200 copies/ml) at least once, and Kaplan-Meier (KM) curves and Cox proportional hazards models were used to identify factors associated with sustaining VS and time to virologic failure (VL ≥ 200 copies/ml after achievement of VS). Among the 4311 participants, 95.4% were either virally suppressed at study enrollment or able to achieve VS during the follow-up period. In multivariate analyses, achieving VS was significantly associated with age (aOR: 1.04; 95%CI: 1.03-1.06 per five-year increase) and having a higher CD4 (aOR: 1.05, 95% CI 1.04-1.06 per 100 cells/mm(3)). Patients infected through perinatal transmission were less likely to achieve VS compared to MSM patients (aOR: 0.63, 95% CI 0.51-0.79). Once achieved, most participants (74.4%) sustained VS during follow-up. Blacks and perinatally infected persons were less likely to have sustained VS in KM survival analysis (log rank chi-square p ≤ .001 for both) compared to other races and risk groups. Earlier time to failure was observed among females, Blacks, publically insured, perinatally infected, those with longer standing HIV infection, and those with diagnoses of mental health issues or depression. Among this HIV-infected cohort, most people achieved and maintained VS; however, disparities exist with regard to patient age, race, HIV transmission risk, and co-morbid conditions. Identifying populations with disparate outcomes allows for appropriate targeting of resources to improve outcomes along the care continuum.

Development of a large urban longitudinal HIV clinical cohort using a web-based platform to merge electronically and manually abstracted data from disparate medical record systems: technical challenges and innovative solutions.

OBJECTIVE: Electronic medical records (EMRs) are being increasingly utilized to conduct clinical and epidemiologic research in numerous fields. To monitor and improve care of HIV-infected patients in Washington, DC, one of the most severely affected urban areas in the United States, we developed a city-wide database across 13 clinical sites using electronic data abstraction and manual data entry from EMRs. MATERIALS AND METHODS: To develop this unique longitudinal cohort, a web-based electronic data capture system (Discovere®) was used. An Agile software development methodology was implemented across multiple EMR platforms. Clinical informatics staff worked with information technology specialists from each site to abstract data electronically from each respective site's EMR through an extract, transform, and load process. RESULTS: Since enrollment began in 2011, more than 7000 patients have been enrolled, with longitudinal clinical data available on all patients. Data sets are produced for scientific analyses on a quarterly basis, and benchmarking reports are generated semi-annually enabling each site to compare their participants' clinical status, treatments, and outcomes to the aggregated summaries from all other sites. DISCUSSION: Numerous technical challenges were identified and innovative solutions developed to ensure the successful implementation of the DC Cohort. Central to the success of this project was the broad collaboration established between government, academia, clinics, community, information technology staff, and the patients themselves. CONCLUSIONS: Our experiences may have practical implications for researchers who seek to merge data from diverse clinical databases, and are applicable to the study of health-related issues beyond HIV.

Low bone mineral density and risk of incident fracture in HIV-infected adults.

BACKGROUND: Prevalence rates of low bone mineral density (BMD) and bone fractures are higher among HIV-infected adults compared with the general United States (US) population, but the relationship between BMD and incident fractures in HIV-infected persons has not been well described. METHODS: Dual energy X-ray absorptiometry (DXA) results of the femoral neck of the hip and clinical data were obtained prospectively during 2004-2012 from participants in two HIV cohort studies. Low BMD was defined by a T-score in the interval >-2.5 to <-1.0 (osteopenia) or ≤-2.5 (osteoporosis). We analysed the association of low BMD with risk of subsequent incident fractures, adjusted for sociodemographics, other risk factors and covariables, using multivariable proportional hazards regression. RESULTS: Among 1,006 participants analysed (median age 43 years [IQR 36-49], 83% male, 67% non-Hispanic white, median CD4(+) T-cell count 461 cells/mm(3) [IQR 311-658]), 36% (n=358) had osteopenia and 4% (n=37) osteoporosis; 67 had a prior fracture documented. During 4,068 person-years of observation after DXA scanning, 85 incident fractures occurred, predominantly rib/sternum (n=18), hand (n=14), foot (n=13) and wrist (n=11). In multivariable analyses, osteoporosis (adjusted hazard ratio [aHR] 4.02, 95% CI 2.02, 8.01) and current/prior tobacco use (aHR 1.59, 95% CI 1.02, 2.50) were associated with incident fracture. CONCLUSIONS: In this large sample of HIV-infected adults in the US, low baseline BMD was significantly associated with elevated risk of incident fracture. There is potential value of DXA screening in this population.

A Matter of Perspective: Comparison of the Characteristics of Persons with HIV Infection in the United States from the HIV Outpatient Study, Medical Monitoring Project, and National HIV Surveillance System.

Comparative analyses of the characteristics of persons living with HIV infection (PLWH) in the United States (US) captured in surveillance and other observational databases are few. To explore potential joint data use to guide HIV treatment and prevention in the US, we examined three CDC-funded data sources in 2012: the HIV Outpatient Study (HOPS), a multisite longitudinal cohort; the Medical Monitoring Project (MMP), a probability sample of PLWH receiving medical care; and the National HIV Surveillance System (NHSS), a surveillance system of all PLWH. Overall, data from 1,697 HOPS, 4,901 MMP, and 865,102 NHSS PLWH were analyzed. Compared with the MMP population, HOPS participants were more likely to be older, non-Hispanic/Latino white, not using injection drugs, insured, diagnosed with HIV before 2009, prescribed antiretroviral therapy, and to have most recent CD4+ T-lymphocyte cell count ≥500 cells/mm3 and most recent viral load test<2 00 copies/mL. The MMP population was demographically similar to all PLWH in NHSS, except it tended to be slightly older, HIV diagnosed more recently, and to have AIDS. Our comparative results provide an essential first step for combined epidemiologic data analyses to inform HIV care and prevention for PLWH in the US.

HIV laboratory monitoring reliably identifies persons engaged in care.

BACKGROUND: Attendance at biannual medical encounters has been proposed as a minimum national standard for adequate engagement in HIV care. Using data from the HIV Outpatient Study, we analyzed how well dates of HIV-related laboratory testing correlated with attendance at biannual medical encounters. METHODS: HIV Outpatient Study is an open prospective cohort study of HIV-infected patients receiving outpatient care in the United States. The data set included dates for laboratory measurements and medical encounters. We included patients with at least 1 HIV laboratory test (CD4 cell count or plasma HIV RNA viral load) during 2010-2011. An HIV laboratory test was defined as associated with a medical encounter if it occurred within 3 weeks of the encounter. We assessed the predictive value of HIV laboratory tests as a proxy for adequate engagement in clinical care, defined as having had ≥2 HIV laboratory tests within 1 year and performed >90 days apart. RESULTS: A total of 10,321 HIV laboratory tests were recorded from 2909 patients. Adequate engagement in clinical care based on medical encounters was 88.2% and 77.3% when based on laboratory tests. Using HIV laboratory tests to assess engagement had a sensitivity of 85.7%, specificity of 86.0%, and positive and negative predictive values of 97.9% and 44.5%, respectively. Of the 22.7% classified as not engaged in care by the proxy measure, over half (55.5%) were actually engaged. CONCLUSIONS: Using laboratory monitoring reliably classified persons as engaged in care. Of the 22.7% of patients classified as not engaged in care, most were actually engaged.

Factors associated with cancer incidence and with all-cause mortality after cancer diagnosis among human immunodeficiency virus-infected persons during the combination antiretroviral therapy era.

BACKGROUND: Little is known about survival and factors associated with mortality after cancer diagnosis among persons infected with human immunodeficiency virus (HIV). METHODS: Using Poisson regression, we analyzed incidence rates of acquired immune deficiency syndrome (AIDS)-defining cancers (ADC), non-AIDS-defining infection-related cancers (NADCI), and non-AIDS-defining noninfection-related cancers (NADCNI) among HIV Outpatient Study participants seen at least twice from 1996-2010. All-cause mortality within each cancer category and by calendar period (1996-2000, 2001-2005, 2006-2010) were examined using Kaplan-Meier survival methods and log-rank tests. We identified risk factors for all-cause mortality using multivariable Cox proportional hazard models. RESULTS: Among 8350 patients, 627 were diagnosed with 664 cancers. Over the 3 time periods, the age- and sex-adjusted incidence rates for ADC and NADCNI declined (both P < .001) and for NADCI did not change (P = .13). Five-year survival differed by cancer category (ADC, 54.5%; NADCI, 65.8%; NADCNI, 65.9%; P = .018), as did median CD4 cell count (107, 241, and 420 cells/mm(3); P < .001) and median log10 viral load (4.1, 2.3, and 2.0 copies/mL; P < .001) at cancer diagnosis, respectively. Factors independently associated with increased mortality for ADC were lower nadir CD4 cell count (hazard ratio [HR] = 3.02; 95% confidence interval [CI], 1.39-6.59) and detectable viral load (≥400 copies/mL; HR = 1.72 [95% CI, 1.01-2.94]) and for NADCNI, age (HR = 1.50 [95% CI, 1.16-1.94]), non-Hispanic black race (HR = 1.92 [95% CI, 1.15-3.24]), lower nadir CD4 cell count (HR = 1.77 [95% CI, 1.07-2.94]), detectable viral load (HR = 1.96 [95% CI, 1.18-3.24]), and current or prior tobacco use (HR = 3.18 [95% CI, 1.77-5.74]). CONCLUSIONS: Since 1996, ADC and NADCNI incidence rates have declined. Survival after cancer diagnosis has increased with concomitant increases in CD4 cell count in recent years. Advances in HIV therapy, including early initiation of combination antiretroviral therapy, may help reduce mortality risk among HIV-infected persons with cancer.

Sexual risk behavior and viremia among men who have sex with men in the HIV Outpatient Study, United States, 2007-2010.

BACKGROUND: Recent US data on unsafe sexual behaviors among viremic HIV-infected men who have sex with men (MSM) are limited. METHOD: Using data abstracted from medical records of the participants in the HIV Outpatient Study (HOPS) and a supplemental behavioral survey, we assessed the frequency of high-risk sexual practices among HIV-infected MSM in care and examined the factors associated with risky sexual practices. We also compared the frequency of unprotected anal sex (UAS) with HIV-negative or unknown serostatus partners among viremic (HIV viral load ≥400 copies per milliliter) vs virologically suppressed (HIV viral load <400 copies per milliliter) MSM. RESULTS: Among 902 HIV-infected MSM surveyed, 704 (78%) reported having sex in the past 6 months, of whom 54% reported UAS (37% insertive, 42% receptive) and 40% UAS with a male partner who was HIV-negative or of unknown serostatus (24% insertive, 31% receptive). In multivariable regression with an outcome of engaging in any UAS with a male partner who was HIV-negative or of unknown serostatus, MSM aged <50 years, who reported injection drug use risk, had ≥2 sex partners, and who disclosed their HIV status to some but not to all of their sex partners were more likely to report this practice. Among MSM who reported any UAS, 15% were viremic; frequency of the UAS did not differ between viremic and virologically suppressed MSM. CONCLUSIONS: The high frequency of UAS with HIV-negative or unknown-status partners among HIV-infected MSM in care suggests the need for targeted prevention strategies for this population.

Sadness in the SUN: using computerized screening to analyze correlates of depression and adherence in HIV-infected adults in the United States.

We used a standardized screening tool to examine frequency of depression and its relation to antiretroviral medication adherence among HIV-infected persons on highly active antiretroviral therapy (HAART) in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). This is a prospective observational cohort of 700 HIV-infected patients enrolled between March 2004 and June 2006 in four U.S. cities, who completed a confidential audio computer-assisted self-interview [ACASI] with behavioral risk and health-related questions at baseline and 6-month follow-up visits, including the nine-question PRIME-MD depression screener and a validated 3-day antiretroviral adherence question. Among 539 eligible participants receiving HAART, 14% had depression at baseline (22% women, 12% men). In multivariable analysis using generalized estimating equations (GEE) to account for repeated measurements through 24 months of follow-up, persons who reported depression on a given ACASI were twice as likely to report nonadherence to antiretrovirals on the same ACASI (Odds ratio [OR] 2.02, 95% CI: 1.15, 3.57] for mild/moderate depression versus none); such persons were also less likely to have HIV viral load<400 copies/mL. Self-administered computerized standardized screening tools can identify at-risk individuals with depression who may benefit from interventions to improve antiretroviral adherence.

Immune reconstitution inflammatory syndrome: incidence and implications for mortality.

OBJECTIVE: To describe incidence of immune reconstitution inflammatory syndrome (IRIS) and its association with mortality in a large multisite US HIV-infected cohort applying an objective, comprehensive definition. DESIGN: We studied 2,610 patients seen during 1996-2007 who initiated or resumed highly active combination antiretroviral therapy (cART) and, during the next 6 months, demonstrated a decline in plasma HIV-RNA viral load of at least 0.5 log(10) copies/ml or an increase of at least 50% in CD4 cell count per microliter. We defined IRIS as the diagnosis of a type B or C condition [as per the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition] or any new mucocutaneous disorder during this same 6-month period. METHODS: We assessed the incidence of IRIS and evaluated risk factors for IRIS using conditional logistic regression and for all-cause mortality using proportional hazards models. RESULTS: We identified 370 cases of IRIS (in 276 patients). Median and nadir CD4 cell counts at cART initiation were 90 and 43 cells/µl, respectively; median viral load was 2.7 log(10) copies/ml. The most common IRIS-defining diagnoses were candidiasis (all forms), cytomegalovirus infection, disseminated Mycobacterium avium intracellulare, Pneumocystis pneumonia, varicella zoster, Kaposi's sarcoma and non-Hodgkin lymphoma. Only one case of Mycobacterium tuberculosis was observed. IRIS was independently associated with CD4 cell count less than 50 cells/µl vs. at least 200 cells/µl [odds ratio (OR) 5.0] and a viral load of at least 5.0 log(10) copies vs. less than 4.0 log(10) copies (OR 2.3). IRIS with a type B-defining or type C-defining diagnosis approximately doubled the risk for all-cause mortality. CONCLUSION: In this large US-based HIV-infected cohort, IRIS occurred in 10.6% of patients who responded to effective ART and contributed to increased mortality.

Ongoing sexually transmitted disease acquisition and risk-taking behavior among US HIV-infected patients in primary care: implications for prevention interventions.

BACKGROUND: To better understand the factors associated with HIV- and sexually transmitted disease (STD)-transmitting behavior among HIV-infected persons, we estimated STD prevalence and incidence and associated risk factors among a diverse sample of HIV-infected patients in primary care. METHODS: We analyzed data from 557 participants in the SUN Study, a prospective observational cohort of HIV-infected adults in primary care in 4 US cities. At enrollment and 6 months thereafter, participants completed an audio computer-assisted self-interview about their sexual behavior, and were screened for genitourinary, rectal, and pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections by nucleic acid amplification testing, and for serologic evidence of syphilis. Women provided cervicovaginal samples and men provided urine to screen for Trichomonas vaginalis by polymerase chain reaction. RESULTS: Thirteen percent of participants had a prevalent STD at enrollment and 7% an incident STD 6 months later. The most commonly diagnosed infections were rectal chlamydia, oropharyngeal gonorrhea, and chlamydial urethritis among the men and trichomoniasis among the women. Other than trichomoniasis, 94% of incident STDs were identified in men who have sex with men. Polysubstance abuse other than marijuana, and having ≥4 sex partners in the 6 months before testing were associated with diagnosis of an incident STD. CONCLUSIONS: STDs were commonly diagnosed among contemporary HIV-infected patients receiving routine outpatient care, particularly among sexually active men who have sex with men who used recreational drugs. These findings underscore the need for frequent STD screening, prevention counseling, and substance abuse treatment for HIV-infected persons in care.

Factors associated with initiation of prolonged analgesic use among patients in the HIV Outpatient Study (HOPS).

BACKGROUND: Analgesic use is common but remains poorly described among human immunodeficiency virus (HIV)-infected persons in the highly active antiretroviral therapy era. METHODS: We studied HIV Outpatient Study participants during 1996 to 2008. We used Cox proportional hazards regression to assess variables associated with initiation of prolonged analgesia (≥90 consecutive days of analgesics); logistic regression to explore variables associated with initiation of prolonged opioid analgesia among those taking any prolonged analgesia; and linear regression to determine temporal trends in prolonged analgesia. RESULTS: Among 4180 patients, 931 (22%) initiated prolonged analgesia. Factors independently associated (P<0.05) with prolonged analgesia included: age above 40 years (hazard ratio=1.20), female sex (1.43), injection drug use as an HIV risk factor (1.33), public healthcare payer (1.88), nadir CD4+ less than 200 cells/mm (1.29), tobacco use (1.43), prior opportunistic infection(s) (1.25), antidepressant use (1.76), and anxiolytic use (1.51). Independent correlates of prolonged opioid analgesia were white race (odds ratio=1.64), baseline CD4+ less than 350 cells/mm (1.88), and anxiolytic use (1.87). Prolonged analgesia ranged from 11% to 15% each year. CONCLUSIONS: In the highly active antiretroviral therapy era, up to 15% of HIV Outpatient Study patients used prolonged analgesic therapy each year. Variables associated with the initiation of prolonged analgesia included HIV and non-HIV-related factors.

Rates and correlates of influenza vaccination among HIV-infected adults in the HIV Outpatient Study (HOPS), USA, 1999-2008.

BACKGROUND: We sought to describe rates of vaccination among HIV-infected adults in care and identify factors associated with vaccination. METHODS: Using data abstracted from medical records of participants in the HIV Outpatient Study (HOPS) during 8 influenza seasons (1999-2008) and negative binomial models with generalized estimating equation methods, we examined factors associated with increased prevalence of annual influenza vaccination. RESULTS: Among active patients, 25.8% to 43.3% were vaccinated for influenza each year (annual mean=35%, test for trend p=0.71). Vaccination rates peaked in October and November of each season and decreased sharply thereafter. In multivariable analysis, patients who were male (67.2%), non-Hispanic white (70%) or Hispanic (66%), had lower HIV viral loads (73.5%), were prescribed antiretroviral treatment (72.7%), or had a greater number of clinical encounters per year (86.7%) were more likely to receive influenza vaccination. DISCUSSION: The decreased likelihood of vaccination among women and non-Hispanic black patients suggests the need for focused efforts to reduce disparities. Increasing patient and clinician education on the importance of universal vaccination, and ensuring that vaccination activities continue in HIV clinics during the later months of the influenza season may improve influenza vaccine coverage.

Factors associated with non-adherence to antiretroviral therapy in the SUN study.

BACKGROUND: Adherence of 95% or greater to highly active combination antiretroviral therapy is generally considered necessary to achieve optimal virologic suppression in HIV-infected patients. Understanding factors associated with poor adherence is essential to improve patient compliance, maximize virologic suppression, and reduce morbidity and mortality. METHODS: We evaluated baseline data from 528 patients taking antiretrovirals, enrolled from March 2004 to June 2006, in a multicenter, longitudinal, prospective cohort study (the SUN study). Using multiple logistic regression, we examined independent risk factors for non-adherence, defined as reporting having missed one or more antiretroviral doses in the past three days on the baseline questionnaire. RESULTS: Of 528 participants (22% female, 28% black, median age 41 years, and median CD4 cell count 486 cells/mm(3)), 85 (16%) were non-adherent. In the final parsimonious multivariate model, factors independently associated with non-adherence included black race (adjusted odds ratio (aOR): 2.08, 95% confidence interval (CI): 1.20-3.60 vs. white race), being unemployed and looking for work (aOR: 2.03, 95% CI: 1.14-3.61 vs. all other employment categories), having been diagnosed with HIV ≥5 years ago (aOR: 1.95, 95% CI: 1.18-3.24 vs. being HIV-diagnosed <5 years ago), drinking three or more drinks per day (aOR: 1.73, 95% CI: 1.02-2.91 vs. drinking <3 drinks per day), and having not engaged in any aerobic exercise in the last 30 days (aOR: 2.13, 95% CI: 1.25-3.57). CONCLUSION: Although the above factors may not be causally related to non-adherence, they might serve as proxies for identifying HIV-infected patients at greatest risk for non-adherence who may benefit from additional adherence support.

Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study.

BACKGROUND: Traditional cardiovascular disease (CVD) risk factors, human immunodeficiency virus (HIV) infection, and antiretroviral (ARV) agents have been associated with CVD events in HIV-infected patients. We investigated the association of low CD4(+) T lymphocyte cell count with incident CVD in a cohort of outpatients treated in 10 HIV specialty clinics in the United States. METHODS: We studied patients who were under observation from 1 January 2002 (baseline), categorized them according to National Cholesterol Education Program guidelines into 10-year cardiovascular risk score (10-y CVR) groups , and observed them until CVD event, death, last HIV Outpatient Study contact, or 30 September 2009. We calculated rates of incident CVD events and identified associated baseline risk factors using Cox proportional hazard models. We also performed a nested case-control study to examine the association of latest CD4(+) cell count with CVD events. RESULTS: Among 2005 patients, 148 experienced incident CVD events. CVD incidence increased steadily from 0.4 to 3.0 events per 100 person-years from lowest to highest 10-y CVR group (P < .001). In multivariable Cox analyses adjusted for 10-y CVR, CD4(+) cell count <350 cells/mm(3) was associated with incident CVD events (hazard ratio, 1.58 [95% confidence interval, 1.09-2.30], compared with >500 cells/mm(3)), suggesting an attributable risk of approximately 20%. In the multivariable case-control analyses, traditional CVD risk factors and latest CD4(+) cell count <500 cells/mm(3), but not cumulative use of ARV class or individual drugs, were associated with higher odds of experiencing CVD events. CONCLUSION: CD4(+) count <500 cells/mm(3) is an independent risk factor for incident CVD, comparable in attributable risk to several traditional CVD risk factors in the HIV Outpatient Study cohort.

Renal function in patients with preexisting renal disease receiving tenofovir-containing highly active antiretroviral therapy in the HIV outpatient study.

Few data exist on the safety of tenofovir (TDF) in HIV-infected patients with preexisting renal dysfunction. We report 12-month changes in renal profiles among 19 such patients (6 patients with history of and 13 patients with current renal disease) in the HIV Outpatient Study (HOPS) who initiated TDF-containing highly active antiretroviral therapy (HAART) during 2001-2005 with TDF dosed mostly at 300 mg once daily. At baseline, the median estimated glomerular filtration rate (GFR) was 49 mL/min/1.73 m(2) and the median CD4(+) cell count was 322 cells/mm(3). Patients had a median 12-month change in estimated creatinine clearance from baseline of -0.3 mL/min (range, -32.2 to +23.6) and the median change in GFR of -0.1 mL/min/1.73 m(2) (range, -49.8 to +29.5). We observed confirmed worsening of kidney disease stage in 5 of the 19 patients during follow-up. TDF use can be considered in patients with preexisting or current renal dysfunction who have limited antiretroviral treatment options, require TDF for fully active antiretroviral regimen, and can be closely monitored for incident worsening of renal function.

Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure.

BACKGROUND: There are limited data on the risk of developing HIV drug resistance based on the CD4 cell count at which highly active antiretroviral therapy (HAART) is initiated. METHODS: We examined data from participants in the HIV Outpatient Study who initiated antiretroviral therapy with HAART in 1999 or later (when genotypic resistance testing became more commonly used in clinical practice and in the HIV Outpatient Study), achieved virologic suppression, and subsequently experienced virologic failure and received a genotypic assay for antiretroviral resistance mutations. We assessed the frequency of resistance mutations at virologic failure and the differences in the frequencies of mutations by the CD4 stratum at which HAART was initiated using the Cochran-Armitage exact test. RESULTS: Of 683 patients who achieved virologic suppression on a first HAART regimen, 243 had virologic failure and 78 of these had a genotype resistance test done. Among these patients, the frequency of any HIV resistance mutations was 50% among patients who started HAART at 0-199 CD4 cells per cubic millimeter or 200-349 CD4 cells per cubic millimeter compared with 22% among patients who started HAART at >or=350 CD4 cells per cubic millimeter (P = 0.062). The frequency of nucleoside reverse transcriptase inhibitor-associated mutations was 48%, 31%, and 11% among persons who initiated nucleoside reverse transcriptase inhibitor-containing HAART within these respective CD4 cell count strata (P = 0.005). We observed similar trends for nonnucleoside reverse transcriptase inhibitor-associated (P = 0.040) and protease inhibitor-associated (P = 0.063) mutations among persons initiating HAART containing these agents. CONCLUSIONS: Patients failing HAART that was initiated at <350 CD4 cells per cubic millimeter had higher frequencies of resistance mutations to the classes of antiretrovirals to which they had been exposed than failing patients who initiated at >or=350 CD4 cells per cubic millimeter. Initiating HAART at higher CD4 cell counts may decrease the risk of developing treatment-limiting antiretroviral resistance.

The study to understand the natural history of HIV and AIDS in the era of effective therapy (SUN Study).

Treatment of human immunodeficiency virus (HIV) infection with highly active combination antiretroviral therapy has increased survival and shifted the spectrum of HIV-associated morbidity and mortality from opportunistic infections toward a variety of other medical conditions. The prospective cohort Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study) monitors the clinical course of HIV-infected individuals treated with combination antiretroviral therapy in 4 US cities. Every 6 months, clinical assessments, medical record abstraction, audio computer-assisted self-interview, and neurocognitive measurements are completed and blood and urine specimens are banked centrally. At enrollment and periodically thereafter, additional techniques such as anal cytology, dual energy x-ray absorptiometry, carotid ultrasonography, echocardiography, and abdominal and cardiac computed tomography are performed. From March 2004 through June 2006, 700 participants were enrolled; median age was 41 years, 76% were men, 58% were non-Hispanic white, 62% were men who have sex with men, 78% were taking combination antiretroviral therapy (of whom 86% had an HIV viral load of <400 copies/mL), and median CD4+ T-lymphocyte count was 459 cells/mm(3) (interquartile range: 324-660). The SUN Study provides a wealth of data that will inform and improve the clinical management of HIV-infected individuals in the modern era.

Renal function in Tenofovir-exposed and Tenofovir-unexposed patients receiving highly active antiretroviral therapy in the HIV Outpatient Study.

BACKGROUND: Cases of renal dysfunction have been reported in HIV-infected patients taking tenofovir (TDF), but few large studies have examined population-level changes in renal function associated with TDF use in patients in routine care. METHODS: The authors analyzed data from participants in the HIV Outpatient Study (HOPS) who had normal baseline renal function and received >1 month of TDF-containing (n = 593) or TDF-sparing (n = 521) HAART after November 1, 2001. RESULTS: Median baseline CrCl estimated by Cockcroft-Gault equation was 106 mL/min for TDF-exposed and 110 mL/min for TDF-unexposed patients (P = 0.06). In multivariable analyses, 1-year changes in CrCl (mL/min) from baseline were -5.7 among TDF-exposed and 2.6 among TDF-unexposed (P < 0.001). Incident renal disease was diagnosed in 7 TDF-exposed and 3 TDF-unexposed patients. CONCLUSIONS: In this large cohort of HIV-infected outpatients, use of TDF-containing HAART was associated with modest decreases in CrCl during the first year, but not with frequent, clinically significant renal toxicity.

Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling.

RATIONALE: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders. OBJECTIVES: To study the effects of T cells on the development of experimental SPH. METHODS: Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats. CONCLUSIONS: These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.