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Article Reference CD4 count at presentation for HIV care in the United States and Canada: Are those over 50 years more likely to have a delayed presentation?
ABSTRACT: We assessed CD4 count at initial presentation for HIV care among ≥50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to 50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm3) and 95\% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were ≥50-years-old increased from 17\% to 27\% (p-value 0.01). The median CD4 count among ≥50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value 0.01) with both age groups experiencing modest annual improvements over time ( 50-year-olds: 5 [4 , 6] cells/mm3; ≥50-year-olds: 7 [5 , 9] cells/mm3), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13\% vs. 10\%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults ≥50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed.
Article Reference Cohort profile: the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)
Article Reference Competing risk regression models for epidemiologic data
Competing events can preclude the event of interest from occurring in epidemiologic data and can be analyzed by using extensions of survival analysis methods. In this paper, the authors outline 3 regression approaches for estimating 2 key quantities in competing risks analysis: the cause-specific relative hazard ((cs)RH) and the subdistribution relative hazard ((sd)RH). They compare and contrast the structure of the risk sets and the interpretation of parameters obtained with these methods. They also demonstrate the use of these methods with data from the Women's Interagency HIV Study established in 1993, treating time to initiation of highly active antiretroviral therapy or to clinical disease progression as competing events. In our example, women with an injection drug use history were less likely than those without a history of injection drug use to initiate therapy prior to progression to acquired immunodeficiency syndrome or death by both measures of association ((cs)RH = 0.67, 95\% confidence interval: 0.57, 0.80 and (sd)RH = 0.60, 95\% confidence interval: 0.50, 0.71). Moreover, the relative hazards for disease progression prior to treatment were elevated ((cs)RH = 1.71, 95\% confidence interval: 1.37, 2.13 and (sd)RH = 2.01, 95\% confidence interval: 1.62, 2.51). Methods for competing risks should be used by epidemiologists, with the choice of method guided by the scientific question.
Article Reference Effect of early versus deferred antiretroviral therapy for HIV on survival
BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or 500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25\%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75\%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69\%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95\% confidence interval [CI], 1.26 to 2.26; P0.001). In the second analysis involving 9155 patients, 2220 (24\%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76\%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94\% (relative risk, 1.94; 95\% CI, 1.37 to 2.79; P0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
Article Reference Evaluating competing adverse and beneficial outcomes using a mixture model
A competing risk framework occurs when individuals have the potential to experience only one of the several mutually exclusive outcomes. Standard survival methods often overestimate the cumulative incidence of events when competing events are censored. Mixture distributions have been previously applied to the competing risk framework to obtain inferences regarding the subdistribution of an event of interest. Often the competing event is treated as a nuisance, but it may be of interest to compare adverse events against the beneficial outcome when dealing with an intervention. In this paper, methods for using a mixture model to estimate an adverse-benefit ratio curve (ratio of the cumulative incidence curves for the two competing events) and the ratio of the subhazards for the two competing events are presented. A parametric approach is described with some remarks for extending the model to include uncertainty in the event type that occurred, left truncation in order to allow for time-dependent analyses, and uncertainty in the timing of the event resulting in interval censoring. The methods are illustrated with data from an HIV clinical cohort examining whether individuals initiating effective antiretroviral therapy have a greater risk of antiretroviral discontinuation or switching compared with HIV RNA suppression.
Article Reference Evaluation of human immunodeficiency virus biomarkers: inferences from interval and clinical cohort studies
INTRODUCTION Among individuals infected with the human immunodeficiency virus (HIV), biomarkers that predict mortality are also used to determine the time when antiretroviral therapy is initiated. No studies have evaluated the impact of the frequency of marker measurements for either their predictive value of mortality or how they may influence inference of the effect of therapy initiation in analyses from observational data. METHODS We identified 244 persons who were contemporaneously enrolled in both the AIDS Link to the IntraVenous Experience (an interval cohort) and the Johns Hopkins HIV Clinical Cohort between 1995 and 2004. Data from each study were used separately in 2 ways. We applied time-dependent proportional hazards models to examine the predictive associations between markers and mortality, and marginal structural models to examine the causal inference of therapy on mortality. Biomarkers were used to derive the inverse probability weights. RESULTS The timing frequencies of marker measurements in the interval cohort (CD4 interquartile range = 175-194 days) were less heterogeneous than in the clinical cohort (interquartile range = 38-121 days). Despite this, the results were concordant for CD4 (R = 0.537 [95\% confidence interval = 0.345-0.707] and (R = 0.488 [0.297-0.666], respectively). Similar concordance was found for the HIV-1 RNA and hemoglobin analyses. When evaluating the causal effect of highly active antiretroviral therapy (HAART), the relative hazards were 0.34 for the interval cohort study (95\% CI = 0.15-0.77) and 0.27 for the clinical cohort study (0.11-0.66). CONCLUSION Utilizing a unique co-enrollment of patients in 2 different types of cohort studies, we find empirical evidence that inferences drawn from these different structures are similar.
Article Reference Identifying individuals with virologic failure after initiating effective antiretroviral therapy: The surprising value of mean corpuscular hemoglobin in a cross-sectional study
UNLABELLED ABSTRACT: OBJECTIVE Recent studies have shown that the current guidelines suggesting immunologic monitoring to determine response to highly active antiretroviral therapy (HAART) are inadequate. We assessed whether routinely collected clinical markers could improve prediction of concurrent HIV RNA levels. METHODS We included individuals followed within the Johns Hopkins HIV Clinical Cohort who initiated antiretroviral therapy and had concurrent HIV RNA and biomarker measurements /=4 months after HAART. A two tiered approach to determine whether clinical markers could improve prediction included: 1) identification of predictors of HIV RNA levels 500 copies/ml and 2) construction and validation of a prediction model. RESULTS Three markers (mean corpuscular hemoglobin [MCH], CD4, and change in percent CD4 from pre-HAART levels) in addition to the change in MCH from pre-HAART levels contained the most predictive information for identifying an HIV RNA 500 copies/ml. However, MCH and change in MCH were the two most predictive followed by CD4 and change in percent CD4. The logistic prediction model in the validation data had an area under the receiver operating characteristic curve of 0.85, and a sensitivity and specificity of 0.74 (95\% CI: 0.69-0.79) and 0.89 (95\% CI: 0.86-0.91), respectively. CONCLUSIONS Immunologic criteria have been shown to be a poor guideline for identifying individuals with high HIV RNA levels. MCH and change in MCH were the strongest predictors of HIV RNA levels 500. When combined with CD4 and percent CD4 as covariates in a model, a high level of discrimination between those with and without HIV RNA levels 500 was obtained. These data suggest an unexplored relationship between HIV RNA and MCH.
Article Reference Interval and clinical cohort studies: epidemiological issues
Cohort studies based upon clinic populations and medical records are becoming more abundant due in part to an increasing trend toward electronic medical records and advancement in information technology. This design has been utilized in the HIV setting to great success and involves following individuals as they access medical care. These clinical cohort designs have not been compared to the classic interval cohort design in which individuals are followed at specified intervals that are unrelated to the participants' ongoing health care. The interval and clinical cohort designs are distinguished and the advantages and disadvantages inherent in each design are discussed.
Article Reference Late presentation for human immunodeficiency virus care in the United States and Canada
BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. 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) count 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/mm(3)) and 95\% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26\% to 14\%; P .01) and heterosexual transmission risk increased (from 16\% to 23\%; P .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P .01). The percentage of patients with a CD4 count or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38\% to 46\%; P .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95\% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained 350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.
Article Reference Trends in Multidrug Treatment Failure and Subsequent Mortality among Antiretroviral Therapy-Experienced Patients with HIV Infection in North America
Background. Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined.Methods. Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level 1000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure.Results. Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P.001). The cumulative mortality after onset of second virologic failure was 26\% at 5 years and decreased over time. A history of AIDS, a lower CD4+T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patientsConclusions. Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4+T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions.
Article Reference Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study
OBJECTIVE To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development. DESIGN Retrospective analysis of a multicenter, prospective natural history study including 4498 HIV-infected US military beneficiaries with 33 486 person-years of follow-up. METHODS Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre (1984-1990), late pre (1991-1995), early post (1996-2000), and late post (2001-2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer. RESULTS Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person-years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (P 0.001). Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7, P = 0.0004). During the late HAART era, 71\% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, noncancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age and white race (due to skin cancers). CONCLUSION Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART use is protective for ADCs, but did not significantly impact NADCs.
Article Reference Virologic and immunologic response to HAART, by age and regimen class
OBJECTIVE To determine the impact of age and initial HAART regimen class on virologic and immunologic response within 24 months after initiation. DESIGN Pooled analysis of data from 19 prospective cohort studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). METHODS Twelve thousand, one hundred and ninety-six antiretroviral-naive adults who initiated HAART between 1998 and 2008 using a boosted protease inhibitor-based regimen or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were included in our study. Discrete time-to-event models estimated adjusted hazard odds ratios (aHOR) and 95\% confidence intervals (CIs) for suppressed viral load (≤500 copies/ml) and, separately, at least 100 cells/μl increase in CD4 cell count. Truncated, stabilized inverse probability weights accounted for selection biases from discontinuation of initial regimen class. RESULTS Among 12 196 eligible participants (mean age = 42 years), 50\% changed regimen classes after initiation (57 and 48\% of whom initiated protease inhibitor and NNRTI-based regimens, respectively). Mean CD4 cell count at initiation was similar by age. Virologic response to treatment was less likely in those initiating using a boosted protease inhibitor [aHOR = 0.77 (0.73, 0.82)], regardless of age. Immunologic response decreased with increasing age [18-30: ref; 30-40: aHOR = 0.92 (0.85, 1.00); 40-50: aHOR = 0.85 (0.78, 0.92); 50-60: aHOR = 0.82 (0.74, 0.90); ≥60: aHOR = 0.74 (0.65, 0.85)], regardless of initial regimen. CONCLUSION We found no evidence of an interaction between age and initial antiretroviral regimen on virologic or immunologic response to HAART; however, decreased immunologic response with increasing age may have implications for age-specific when-to-start guidelines.
Article Reference When to start antiretroviral therapy
The question of when to initiate antiretroviral therapy has been a central controversy in HIV management for more than 15 years, yet there are limited data from randomized controlled trials addressing it. A major obstacle to performing such a study is the need for large numbers of asymptomatic, antiretroviral therapy-naive individuals observed over many years beginning from when their CD4+ cell counts are above 500/mm3. Observational cohort studies with substantial person-years of follow-up have informed this debate in the absence of randomized trials. Emerging evidence regarding the damage caused by untreated HIV infection-related inflammation and immune activation at all stages of disease, and the benefits of modern antiretroviral therapy in preventing both AIDS- and non-AIDS-related morbidity and mortality has supported a return to starting treatment early. The NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) study compared long-term outcomes of immediate versus deferred therapy at 2 CD4+ cell count thresholds. Results showed a 94\% increased risk of all-cause mortality when antiretroviral therapy was deferred at CD4+ cell counts greater than 500/mm3. This article summarizes presentations made by Mari M. Kitahata, MD, MPH, at the International AIDS Society-USA continuing medical education programs held in November 2009 in New York City and May 2010 in San Francisco. The original presentations are available as Webcasts at www.iasusa.org.
Article Reference Risk factors for tuberculosis after highly active antiretroviral therapy initiation in the United States and Canada: implications for tuberculosis screening.
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.