Association between U.S. state AIDS Drug Assistance Program (ADAP) features and HIV antiretroviral therapy initiation, 2001-2009.

BACKGROUND: U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes. METHODS: We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU). RESULTS: Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60-0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87-1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47-0.95). CONCLUSIONS: We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.

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.

BACKGROUND: 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). OBJECTIVE: 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. DESIGN: 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. SETTING: U.S. HIV outpatient clinics. PATIENTS: 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. MEASUREMENTS: Annual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death. RESULTS: 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). LIMITATION: The usual limitations of observational data apply. CONCLUSION: 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.

Estimation and inference on correlations between biomarkers with repeated measures and left-censoring due to minimum detection levels.

Statistical approaches for estimating and drawing inference on the correlation between two biomarkers that are repeatedly assessed over time and subject to left-censoring because minimum detection levels are lacking. We propose a linear mixed-effects model and estimate the parameters with the Monte Carlo expectation maximization (MCEM) method. Inferences regarding the model parameters and the correlation between the biomarkers are performed by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCEM method with existing methods including the maximum likelihood estimation method, the multiple imputation method, and two widely used ad hoc approaches: replacing the censored values with the detection limit or with half of the detection limit. The results show that the performance of the MCEM with respect to relative bias and coverage probability for the 95% confidence interval is superior to the detection limit and half of the detection limit approaches and exceeds that of the multiple imputation method at medium to high levels of censoring, and the standard error estimates from the MCEM method are close to ideal. The maximum likelihood estimation method can estimate the parameters accurately; however, a nonpositive definite information matrix can occur so that the variances are not estimable. These five methods are illustrated with data from a longitudinal human immunodeficiency virus study to estimate and draw inference on the correlation between human immunodeficiency virus RNA levels measured in plasma and in cervical secretions at multiple time points.

Disparities among US states in HIV-related mortality in persons with HIV infection, 2001-2007.

OBJECTIVE: To examine interstate variation in US HIV case-fatality rates, and compare them with corresponding conventional HIV death rates. DESIGN: Cross-sectional analysis using data on deaths due to HIV infection from the National Vital Statistics System and data on persons 15 years or older living with HIV infection in 2001-2007 in 37 US states from the national HIV/AIDS Reporting System. METHODS: State rankings by age-adjusted HIV case-fatality rates (with HIV-infected population denominators) were compared with rankings by conventional death rates (with general population denominators). Negative binomial regression determined case-fatality rate ratios among states, adjusted for age, sex, race/ethnicity, year, and state-level markers of late HIV diagnosis. RESULTS: On the basis of 3,096,729 HIV-infected person-years, the overall HIV case-fatality rate was 20.6 per 1000 person-years [95% confidence interval (CI) 20.3-20.9]. Age-adjusted rates by state ranged from 9.6 (95% CI 6.8-12.4) in Idaho to 32.9 (95% CI 29.8-36.0) in Mississippi, demonstrating significant differences across states, even after adjusting for race/ethnicity (P < 0.0001). Many states with low conventional death rates had high case-fatality rates. Nine of the 10 states with the highest case-fatality rates were located in the southern United States. CONCLUSION: Case-fatality rates complement and are not entirely concordant with conventional death rates. Interstate differences in these rates may reflect differences in secondary and tertiary prevention of HIV-related mortality among infected persons. These data suggest that state-specific contextual barriers to care may impede improvements in quality and disparities of healthcare without targeted interventions.

Computer-aided assessment of diagnostic images for epidemiological research.

BACKGROUND: Diagnostic images are often assessed for clinical outcomes using subjective methods, which are limited by the skill of the reviewer. Computer-aided diagnosis (CAD) algorithms that assist reviewers in their decisions concerning outcomes have been developed to increase sensitivity and specificity in the clinical setting. However, these systems have not been well utilized in research settings to improve the measurement of clinical endpoints. Reductions in bias through their use could have important implications for etiologic research. METHODS: Using the example of cortical cataract detection, we developed an algorithm for assisting a reviewer in evaluating digital images for the presence and severity of lesions. Available image processing and statistical methods that were easily implementable were used as the basis for the CAD algorithm. The performance of the system was compared to the subjective assessment of five reviewers using 60 simulated images. Cortical cataract severity scores from 0 to 16 were assigned to the images by the reviewers and the CAD system, with each image assessed twice to obtain a measure of variability. Image characteristics that affected reviewer bias were also assessed by systematically varying the appearance of the simulated images. RESULTS: The algorithm yielded severity scores with smaller bias on images where cataract severity was mild to moderate (approximately

Longitudinal assessment of de novo T cell production in relation to HIV-associated T cell homeostasis failure.

Loss of circulating CD4+ T cells in HIV-1 disease is balanced by CD8+ lymphocytosis to maintain normal CD3+ T cell counts [blind T cell homeostasis (TCH)]. However, for unknown reasons TCH generally fails 1.5-2.5 years before clinically defined AIDS. We investigated whether TCH failure was associated with changes in thymic production of T cells. Using specimens stored prospectively in the Multicenter AIDS Cohort Study (MACS), we measured expression of signal-joint T cell receptor excision circles (sjTRECs), a marker for thymic T cell production, and the fraction of proliferating naive and memory T cells during a 6-8 year period bracketing TCH failure. Segmented regression modeling assessed (1) rates of change in TREC levels before and after TCH failure, and (2) whether these were affected by cellular proliferation, which may dilute sjTREC levels. TCH failure was associated with a large decline in sjTREC (median 1109-fold, p = 0.028); the rate of this decline was only slightly affected when increased proliferation of naive T cells or other peripheral lymphocytes was taken into account. Preferential loss of naive CD4+ T cells was also noted before TCH failure, as has been seen in other studies. These results suggest that deficits in de novo T cell production, either through the decline of thymic function or the destruction of naive T cells, are likely to play an important role in TCH failure and progression of HIV-1 disease.

Screening HIV-positive pregnant women for antiretroviral therapy: utility of self-reported symptoms.

In developing countries, Mother-to-Child Transmission-Plus programmes propose to identify lifelong antiretroviral therapy (ART)-eligible women during antenatal care. Identification using AIDS-related symptoms is the most feasible screening procedure in resource-limited settings. It is not known if symptomatology in pregnant women is correlated with clinical criteria for ART initiation based on CD(4)+ cell count or HIV-1 viral load. In this population of HIV-positive pregnant women from Rakai District, Uganda, 8-23% were eligible for treatment by CD(4)+ cell count criteria, and <1% met WHO staging criteria for AIDS. Using one or more symptoms to predict CD(4)+ cell count <350 cells/mm(3), sensitivity was 100%, specificity 11%, positive predictive value (PPV) 25%, and negative predictive value (NPV) 100%. When using one or more symptoms to predict viral load > or =100,000 cps/mL, sensitivity was 100%, specificity 10%, PPV 6%, and NPV 100%. Initiation of treatment based on self-reported symptoms will over-treat because the majority of pregnant women with symptoms would not be eligible for treatment under current guidelines, but asymptomatic pregnant women are unlikely to require ART.