James H. Willig

Missed Visits and Mortality among Patients Establishing Initial Outpatient HIV Treatment

BACKGROUND Dramatic increases in the number of patients requiring linkage to treatment for human immunodeficiency virus (HIV) infection are anticipated in response to updated Centers for Disease Control and Prevention HIV testing recommendations that advocate routine, opt-out HIV testing. METHODS A retrospective analysis nested within a prospective HIV clinical cohort study evaluated patients who established initial outpatient treatment for HIV infection at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic from 1 January 2000 through 31 December 2005. Survival methods were used to evaluate the impact of missed visits during the first year of care on subsequent mortality in the context of other baseline sociodemographic, psychosocial, and clinical factors. Mortality was ascertained by query of the Social Security Death Index as of 1 August 2007. RESULTS Among 543 study participants initiating outpatient care for HIV infection, 60% missed a visit within the first year. The mortality rate was 2.3 deaths per 100 person-years for patients who missed visits, compared with 1.0 deaths per 100 person-years for those who attended all scheduled appointments during the first year after establishing outpatient treatment (P = .02). In Cox proportional hazards analysis, higher hazards of death were independently associated with missed visits (hazard ratio, 2.90; 95% confidence interval, 1.28-6.56), older age (hazard ratio, 1.58 per 10 years of age; 95% confidence interval, 1.12-2.22), and baseline CD4+ cell count < 200 cells/mm(3) (hazard ratio, 2.70; 95% confidence interval, 1.00-7.30). CONCLUSIONS Patients who missed visits within the first year after initiating outpatient treatment for HIV infection had more than twice the rate of long-term mortality, compared with those patients who attended all scheduled appointments. We posit that early missed visits are not causally responsible for the higher observed mortality but, rather, identify those patients who are more likely to exhibit health behaviors that portend increased subsequent mortality.

The Therapeutic Implications of Timely Linkage and Early Retention in HIV Care

Following HIV diagnosis, linkage to outpatient treatment, antiretroviral initiation, and longitudinal retention in care represent the foundation for successful treatment. While prior studies have evaluated these processes in isolation, a systematic evaluation of successive steps in the same cohort of patients has not yet been performed. To ensure optimal long-term outcomes, a better understanding of the interplay of these processes is needed. Therefore, a retrospective cohort study of patients initiating outpatient care at the University of Alabama at Birmingham 1917 HIV=AIDS Clinic between January 2000 and December 2005 was undertaken. Multivariable models determined factors associated with: late diagnosis=linkage to care (initial CD4 < 350 cells=mm3), timely antiretroviral initiation, and retention across the first two years of care. Delayed linkage was observed in two-thirds of the overall sample (n = 567) and was associated with older age (odds ratio [OR] = 1.31 per 10 years; 95%confidence interval [CI] = 1.06-1.62) and African American race (OR = 2.45; 95% CI = 1.60-3.74). Attending all clinic visits (hazard ratio [HR] = 6.45; 95% CI = 4.47-9.31) and lower initial CD4 counts led to earlier antiretroviral initiation. Worse retention in the first 2 years was associated with younger age (OR = 0.68 per 10 years;95% CI = 0.56-0.83), higher baseline CD4 count, and substance abuse (OR = 1.78; 95% CI = 1.16-2.73). Interventions to improve timely HIV diagnosis and linkage to care should focus on older patients and African Americans while efforts to improve retention should address younger patients, those with higher baseline CD4 counts, and substance abuse. Missed clinic visits represent an important obstacle to the timely initiation of antiretroviral therapy. These data inform development of interventions to improve linkage and retention in HIV care, an emerging area of growing importance.

Early Retention in HIV Care and Viral Load Suppression: Implications for a Test and Treat Approach to HIV Prevention

BackgroundAfter HIV diagnosis and linkage to care, achieving and sustaining viral load (VL) suppression has implications for patient outcomes and secondary HIV prevention. We evaluated factors associated with expeditious VL suppression and cumulative VL burden among patients establishing outpatient HIV care. MethodsPatients initiating HIV medical care from January 2007 to October 2010 at the University of Alabama at Birmingham and University of Washington were included. Multivariable Cox proportional hazards and linear regression models were used to evaluate factors associated with time to VL suppression (<50 copies/mL) and cumulative VL burden, respectively. Viremia copy-years, a novel area under the longitudinal VL curve measure, was used to estimate 2-year cumulative VL burden from clinic enrollment. ResultsAmong 676 patients, 63% achieved VL <50 copies per milliliter in a median 308 days. In multivariable analysis, patients with more time-updated “no show” visits experienced delayed VL suppression (hazard ratio = 0.84 per “no show” visit, 95% confidence interval = 0.76 to 0.92). In multivariable linear regression, visit nonadherence was independently associated with greater cumulative VL burden (log10 viremia copy-years) during the first 2 years in care (Beta coefficient = 0.11 per 10% visit nonadherence, 95% confidence interval = 0.04 to 0.17). Across increasing visit adherence categories, lower cumulative VL burden was observed (mean ± standard deviation log10 copy × years/mL); 0%–79% adherence: 4.6 ± 0.8; 80%–99% adherence: 4.3 ± 0.7; and 100% adherence: 4.1 ± 0.7 log10 copy × years/mL, respectively (P < 0.01). ConclusionsHigher rates of early retention in HIV care are associated with achieving VL suppression and lower cumulative VL burden. These findings are germane for a test and treat approach to HIV prevention.

Measuring Retention in HIV Care: The Elusive Gold Standard

Background:Measuring retention in HIV primary care is complex, as care includes multiple visits scheduled at varying intervals over time. We evaluated 6 commonly used retention measures in predicting viral load (VL) suppression and the correlation among measures. Methods:Clinic-wide patient-level data from 6 academic HIV clinics were used for 12 months preceding implementation of the Centers for Disease Control and Prevention/Health Resources and Services Administration (CDC/HRSA) retention in care intervention. Six retention measures were calculated for each patient based on scheduled primary HIV provider visits: count and dichotomous missed visits, visit adherence, 6-month gap, 4-month visit constancy, and the HRSA HIV/AIDS Bureau (HRSA HAB) retention measure. Spearman correlation coefficients and separate unadjusted logistic regression models compared retention measures with one another and with 12-month VL suppression, respectively. The discriminatory capacity of each measure was assessed with the c-statistic. Results:Among 10,053 patients, 8235 (82%) had 12-month VL measures, with 6304 (77%) achieving suppression (VL <400 copies/mL). All 6 retention measures were significantly associated (P < 0.0001) with VL suppression (odds ratio; 95% CI, c-statistic): missed visit count (0.73; 0.71 to 0.75, 0.67), missed visit dichotomous (3.2; 2.8 to 3.6, 0.62), visit adherence (3.9; 3.5 to 4.3,0.69), gap (3.0; 2.6 to 3.3, 0.61), visit constancy (2.8; 2.5 to 3.0, 0.63), and HRSA HAB (3.8; 3.3 to 4.4, 0.59). Measures incorporating “no-show” visits were highly correlated (Spearman coefficient = 0.83–0.85), as were measures based solely on kept visits (Spearman coefficient = 0.72–0.77). Correlation coefficients were lower across these 2 groups of measures (range = 0.16–0.57). Conclusions:Six retention measures displayed a wide range of correlation with one another, yet each measure had significant association and modest discrimination for VL suppression. These data suggest there is no clear gold standard and that selection of a retention measure may be tailored to context.

Aging With HIV: A Cross-Sectional Study of Comorbidity Prevalence and Clinical Characteristics Across Decades of Life

&NA; Nurses and nurse practitioners require information on the health problems faced by aging HIV‐infected adults. In this descriptive, cross‐sectional study, we reviewed the electronic medical records of 1,478 adult patients seen in an HIV clinic between May 2006 and August 2007 to examine patterns of comorbidities, and immunological and clinical characteristics across each decade of life. With increasing age, patients were found to have lower HIV viral loads, more prescribed medications, and a higher prevalence of comorbid conditions, including coronary artery disease, hypertension, hypercholesterolemia, hypogonadism, erectile dysfunction, diabetes, peripheral neuropathy, hepatitis C, esophageal gastric reflux disease, and renal disease. Fortunately, with increasing age, patients were also more likely to have public or private health insurance and tended to be more compliant to medical appointments. With growing interest in aging with HIV, this study highlights the vastly different comorbidity profiles across decades of life, calling into question what constitutes “older” with HIV.

Racial disparities in HIV virologic failure: Do missed visits matter?

Background:Racial/ethnic health care disparities are well described in people living with HIV/AIDS, although the processes underlying observed disparities are not well elucidated. Methods:A retrospective analysis nested in the University of Alabama at Birmingham 1917 Clinic Cohort observational HIV study evaluated patients between August 2004 and January 2007. Factors associated with appointment nonadherence, a proportion of missed outpatient visits, were evaluated. Next, the role of appointment nonadherence in explaining the relationship between African American race and virologic failure (plasma HIV RNA >50 copies/mL) was examined using a staged multivariable modeling approach. Results:Among 1221 participants, a broad distribution of appointment nonadherence was observed, with 40% of patients missing at least 1 in every 4 scheduled visits. The adjusted odds of appointment nonadherence were 1.85 times higher in African American patients compared with whites [95% confidence interval (CI) = 1.61 to 2.14]. Appointment nonadherence was associated with virologic failure (odds ratio = 1.78, 95% CI = 1.48 to 2.13) and partially mediated the relationship between African American race and virologic failure. African Americans had 1.56 times the adjusted odds of virologic failure (95% CI = 1.19 to 2.05), which declined to 1.30 (95% CI = 0.98 to 1.72) when controlling for appointment nonadherence, a hypothesized mediator. Conclusions:Appointment nonadherence was more common in African American patients, associated with virologic failure, and seemed to explain part of observed racial disparities in virologic failure.

Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy

Introduction:Data on initial antiretroviral regimen longevity predates the arrival of newer nucleoside reverse transcriptase inhibitor backbones and once-daily regimens. Modern regimens are thought to possess greater tolerability and convenience. We hypothesized this would translate into greater durability. Methods:Retrospective study of antiretroviral-naive patients starting treatment at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic 1 January 2000–31 July 2007. Two periods of antiretroviral initiation were identified, prior and after August 2004 (arrival of once-daily fixed-dose regimens). Kaplan–Meier survival analyses of regimen durability by time period and regimen characteristics were performed. Staged Cox proportional hazards models evaluated the roles of dosing complexity and composition in explaining differences in regimen durability between study periods. Results:Overall 542 patients started antiretroviral drugs (n = 309, January 2000–July 2004; n = 233, August 2004–July 2007). Median durability was 263 days longer in after August 2004 regimens. Regimens started before August 2004 had increased hazards for discontinuation relative to after August 2004 regimens [hazard ratio (HR) = 1.44; 95% confidence interval (CI) = 1.03–2.02]. Time period of initiation lost statistical significance when the model included dosing frequency (HR = 1.92 for at least twice daily vs. daily; 95% CI = 1.29–2.88). As regimen composition variables were added, time period and dosing frequency lost significance. Increased hazards of discontinuation were observed with didanosine or stavudine relative to abacavir or tenofovir use (HR = 1.92; 95% CI = 1.29–2.88) and all third drugs compared with non-nucleoside reverse transcriptase inhibitor-based regimens (triple-nucleoside reverse transcriptase inhibitor HR = 1.76; 95% CI = 1.14–2.73; unboosted-protease inhibitor HR = 1.58; 95% CI = 1.02–2.46; boosted-protease inhibitor HR = 1.57; 95% CI = 1.02–2.41). Affective mental health disorders increased the hazard of discontinuation in all models. ConclusionDurability of contemporary once-daily fixed-dose antiretroviral regimens has significantly eclipsed the duration of earlier antiretroviral drug options. Our results indicate this is due to both more convenient dosing and improved tolerability of modern antiretroviral regimens.

Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care

Objective:To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART. Methods:Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes. Results:Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type. Conclusion:ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.

Predictive accuracy of the veterans aging cohort study index for mortality with HIV infection: A north american cross cohort analysis

Background:By supplementing an index composed of HIV biomarkers and age (restricted index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) index more completely reflects risk of mortality. We compare the accuracy of the VACS and restricted indices (1) among subjects outside the Veterans Affairs Healthcare System, (2) more than 1–5 years of prior exposure to antiretroviral therapy (ART), and (3) within important patient subgroups. Methods:We used data from 13 cohorts in the North American AIDS Cohort Collaboration (n = 10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine, and hepatitis C status), and survival. We used C-statistics and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1 to 5 years. We then combined Veterans Affairs Healthcare System (n = 5066) and North American AIDS Cohort Collaboration data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results:Mean follow-up was 3.3 years (655 deaths). Compared with the restricted index, the VACS index showed greater discrimination (C-statistics: 0.77 vs. 0.74; NRI: 12%; P < 0.0001). NRI was highest among those with HIV-1 RNA <500 copies per milliliter (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusions:VACS index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposure to ART and for diverse patient subgroups from North American.

Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy.

Background:The prognostic significance of a response to highly active antiretroviral therapy (HAART) that is immunologically and virologically discordant is not well understood. Methods:Four hundred four antiretroviral-naive patients initiating HAART at an urban HIV outpatient clinic in 1995 to 2004 were analyzed. The association of treatment responses at 3 to 9 months after HAART initiation with time to development of an opportunistic infection (OI) or death was determined using Cox proportional hazards modeling. Logistic regression modeling was used to examine the association between discordant responses and patient characteristics. Results:Of 404 patients, 70.5% experienced favorable concordant responses (CD4 cell count [CD4]+/viral load [VL]+: increase in CD4 count of ≥50 cells/μL and achievement of undetectable plasma HIV RNA level), 15.8% an immunologic response only (CD4+/VL−), 8.7% a virologic response only (CD4−/VL+), and 5.0% a concordant unfavorable response (CD4−/VL−). Both types of discordant responses (CD4+/VL− and CD4−/VL+), nonresponse (CD4−/VL−), and baseline CD4 cell count were significantly associated with earlier development of an OI or death (relative hazard [RH] = 2.81, 95% confidence interval [CI]: 1.31 to 3.97; RH = 4.83, 95% CI: 2.10 to 11.12; and RH = 0.93, 95% CI: 0.88 to 0.99, respectively). CD4+/VL− and CD4−/VL− were associated with nonwhite race in multivariate logistic regression models (adjusted OR = 2.83, 95% CI: 1.46 to 5.47 and adjusted OR = 6.50, 95% CI: 1.65 to 25.69, respectively). Conclusion:Discordant immunologic and virologic responses at 3 to 9 months after HAART initiation play important roles in predicting long-term clinical outcomes in treatment-naive patients.