Expression of Small Noncoding RNAs in Urinary Exosomes Classifies Prostate Cancer into Indolent and Aggressive Disease.

PURPOSE: This is the first report of the development and performance of a platform that interrogates small noncoding RNAs (sncRNA) isolated from urinary exosomes. The Sentinel™ PCa Test classifies patients with prostate cancer from subjects with no evidence of prostate cancer, the miR Sentinel CS Test stratifies patients with prostate cancer between those with low risk prostate cancer (Grade Group 1) from those with intermediate and high risk disease (Grade Group 2-5), and the miR Sentinel HG Test stratifies patients with prostate cancer between those with low and favorable intermediate risk prostate cancer (Grade Group 1 or 2) and those with high risk (Grade Group 3-5) disease. MATERIALS AND METHODS: sncRNAs were extracted from urinary exosomes of 235 participants and interrogated on miR 4.0 microarrays. Using proprietary selection and classification algorithms, informative sncRNAs were selected to customize an interrogation OpenArray™ platform that forms the basis of the tests. The tests were validated using a case-control sample of 1,436 subjects. RESULTS: The performance of the miR Sentinel PCa Test demonstrated a sensitivity of 94% and specificity of 92%. The Sentinel CS Test demonstrated a sensitivity of 93% and specificity of 90% for prediction of the presence of Grade Group 2 or greater cancer, and the Sentinel HG Test demonstrated a sensitivity of 94% and specificity of 96% for the prediction of the presence of Grade Group 3 or greater cancer. CONCLUSIONS: The Sentinel PCa, CS and HG Tests demonstrated high levels of sensitivity and specificity, highlighting the utility of interrogation of urinary exosomal sncRNAs for noninvasively diagnosing and classifying prostate cancer with high precision.

Parsimonious covariate selection for a multicategory ordered response.

We propose a flexible continuation ratio (CR) model for an ordinal categorical response with potentially ultrahigh dimensional data that characterizes the unique covariate effects at each response level. The CR model is the logit of the conditional discrete hazard function for each response level given covariates. We propose two modeling strategies, one that keeps the same covariate set for each hazard function but allows regression coefficients to arbitrarily change with response level, and one that allows both the set of covariates and their regression coefficients to arbitrarily change with response. Evaluating a covariate set is accomplished by using the nonparametric bootstrap to estimate prediction error and their robust standard errors that do not rely on proper model specification. To help with interpretation of the selected covariate set, we flexibly estimate the conditional cumulative distribution function given the covariates using the separate hazard function models. The goodness-of-fit of our flexible CR model is assessed with graphical and numerical methods based on the cumulative sum of residuals. Simulation results indicate the methods perform well in finite samples. An application to B-cell acute lymphocytic leukemia data is provided.

The association between antidepressant use and hemoglobin A1C in older adults.

Depression is known to increase diabetes risk and worsen glycemic control in older adults, who already experience high rates of diabetes. The independent impact of antidepressants on glucose control is less clear. Data was drawn from the Health and Retirement Study, a large nationally-representative longitudinal study of retired individuals. Crude and adjusted linear models stratified by diabetes status were used to examine the cross-sectional associations between antidepressant use categorized by subclass and continuous hemoglobin A1C. The sample included 1,153 individuals, most over the age of 70. Antidepressant use was not associated with hemoglobin A1C in any model whether stratified or in the total combined sample. Antidepressants as a class were also not associated with hemoglobin A1C. These findings add to the literature suggesting that antidepressants are not associated with diabetes risk or glycemic control. Prospective studies with larger sample sizes are needed to confirm this finding.

The influence of seasonality and manufacturer kit lot changes on 17α-hydroxyprogesterone measurements and referral rates of congenital adrenal hyperplasia in newborns.

Newborn screening for congenital adrenal hyperplasia (CAH) is performed by measuring the concentration of 17α-hydroxyprogesterone (17-OHP) in dried blood spots. Unfortunately, the level of 17-OHP varies due to multiple factors, and therefore, the false positive rate for the test is a challenge. We analyzed screening data from 2007 to 2015 to determine the effect of seasonal changes and manufacturer kit lot changes on 17-OHP values and on numbers of infants referred. Data from screening 2.2 million infants over a 9-year period indicates that in the NYS during the colder months, daily mean 17-OHP values are higher, more retests are performed, and more infants are referred even though fewer infants are born. The practice of using fixed cutoffs for referring infants for CAH leads to more false positive results in colder months. In addition, there was an overall 10% increase in the daily mean 17-OHP values from the 2 years before and after a manufacturer kit lot change that occurred in November 2013, suggestive of a functional change in the kit at that time. CONCLUSION: Newborn screening programs should be cognizant of seasonal temperature variations and (un)anticipated manufacturer kit changes because they may affect 17-OHP values and CAH referral rates. What is Known: • Newborn screening for congenital adrenal hyperplasia is generally performed by measuring 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. • 17-OHP concentrations are affected by gestational age/weight of infant when specimen is collected, specimen collection time after birth, as well as race and sex of infant. What is New: • Seasonal temperature variations and unanticipated manufacturer kit changes affect 17-OHP levels and consequently referral rates in programs that use fixed cutoffs. • Daily mean 17-OHP is generally higher when the ambient temperature is lower.

Use of antidepressant medications not associated with A1C among individuals with diabetes in NHANES sample.

INTRODUCTION: Studies on the relationships between antidepressant medications and A1C, a measure of glucose levels over the past three months, have resulted in mixed findings. Most available research examined subclass effects. The current study aims to measure the association between individual antidepressant medications and A1C in a large nationally-representative dataset. METHODS: The sample of this study consists of 45,786 individuals who participated in the National Health and Nutrition Examination Survey between 1999 and 2012. We examined the relationships between 18 antidepressant medications and continuous A1C in crude and adjusted linear models stratified by diabetes status (ever or never diagnosed). Adjusted models included demographic covariates (age, gender, race/ethnicity, and education), smoking status, and physical activity. RESULTS: No significant associations were found for most antidepressants. However, those who used selegiline (n=11), all of whom were in the no diabetes stratum, were found to have a higher A1C compared with individuals who do not use antidepressants. DISCUSSION: The study agrees with a number of earlier findings. Most antidepressant medications do not appear to be associated with A1C levels among individuals with or without diabetes. Limitations include small numbers for some exposure categories and cross-sectional data. Strengths include use of a nationally-representative dataset and large total sample size.

Trends with corticosteroid use in males with Duchenne muscular dystrophy born 1982-2001.

This study examines trends in corticosteroid use for males with Duchenne muscular dystrophy by birth year, race/ethnicity, and knowledge of Duchenne muscular dystrophy family history. Firstborn males (n = 521) selected from a population-based surveillance system of Duchenne muscular dystrophy were analyzed using Kaplan Meier and regression methods. Comparing males born 1982 to 1986 with males born 1997 to 2001, steroid use increased from 54% to 72% and mean age at steroid initiation decreased from 8.2 to 7.1 years. Hispanics and non-Hispanic Black males used steroids less frequently and delayed initiation compared to white males. Compared to males without a Duchenne muscular dystrophy family history, males with known family history were half as likely to use steroids. Duration of steroid use increased over time and age at initiation decreased. Racial/ethnic disparities exist for steroid use and should be addressed to improve outcome and quality of life for boys with Duchenne muscular dystrophy.

The association between selenium and other micronutrients and thyroid cancer incidence in the NIH-AARP Diet and Health Study.

BACKGROUND: Selenium is an essential trace element that is important for thyroid hormone metabolism and has antioxidant properties which protect the thyroid gland from oxidative stress. The association of selenium, as well as intake of other micronutrients, with thyroid cancer is unclear. METHODS: We evaluated associations of dietary selenium, beta-carotene, calcium, vitamin D, vitamin C, vitamin E, folate, magnesium, and zinc intake with thyroid cancer risk in the National Institutes of Health - American Association of Retired Persons Diet and Health Study, a large prospective cohort of 566,398 men and women aged 50-71 years in 1995-1996. Multivariable-adjusted Cox proportional hazards regression was used to examine associations between dietary intake of micronutrients, assessed using a food frequency questionnaire, and thyroid cancer cases, ascertained by linkage to state cancer registries and the National Death Index. RESULTS: With the exception of vitamin C, which was associated with an increased risk of thyroid cancer (HR(Q5 vs Q1), 1.34; 95% CI, 1.02-1.76; P(trend), <0.01), we observed no evidence of an association between quintile of selenium (HR(Q5 vs Q1), 1.23; 95% CI, 0.92-1.65; P(trend), 0.26) or other micronutrient intake and thyroid cancer. CONCLUSION: Our study does not suggest strong evidence for an association between dietary intake of selenium or other micronutrients and thyroid cancer risk. More studies are needed to clarify the role of selenium and other micronutrients in thyroid carcinogenesis.

Randomization to screening for prostate, lung, colorectal and ovarian cancers and thyroid cancer incidence in two large cancer screening trials.

BACKGROUND: Thyroid cancer incidence has increased significantly over the past three decades due, in part, to incidental detection. We examined the association between randomization to screening for lung, prostate, colorectal and/or ovarian cancers and thyroid cancer incidence in two large prospective randomized screening trials. METHODS: We assessed the association between randomization to low-dose helical CT scan versus chest x-ray for lung cancer screening and risk of thyroid cancer in the National Lung Screening Trial (NLST). In the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO), we assessed the association between randomization to regular screening for said cancers versus usual medical care and thyroid cancer risk. Over a median 6 and 11 years of follow-up in NLST and PLCO, respectively, we identified 60 incident and 234 incident thyroid cancer cases. Cox proportional hazards regression was used to calculate the cause specific hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer. RESULTS: In NLST, randomization to lung CT scan was associated with a non-significant increase in thyroid cancer risk (HR = 1.61; 95% CI: 0.96-2.71). This association was stronger during the first 3 years of follow-up, during which participants were actively screened (HR = 2.19; 95% CI: 1.07-4.47), but not subsequently (HR = 1.08; 95% CI: 0.49-2.37). In PLCO, randomization to cancer screening compared with usual care was associated with a significant decrease in thyroid cancer risk for men (HR = 0.61; 95% CI: 0.49-0.95) but not women (HR = 0.91; 95% CI: 0.66-1.26). Similar results were observed when restricting to papillary thyroid cancer in both NLST and PLCO. CONCLUSION: Our study suggests that certain medical encounters, such as those using low-dose helical CT scan for lung cancer screening, may increase the detection of incidental thyroid cancer.

Quantifying sources of bias in National Healthcare Safety Network laboratory-identified Clostridium difficile infection rates.

OBJECTIVE: To assess the effect of multiple sources of bias on state- and hospital-specific National Healthcare Safety Network (NHSN) laboratory-identified Clostridium difficile infection (CDI) rates. DESIGN: Sensitivity analysis. SETTING: A total of 124 New York hospitals in 2010. METHODS: New York NHSN CDI events from audited hospitals were matched to New York hospital discharge billing records to obtain additional information on patient age, length of stay, and previous hospital discharges. "Corrected" hospital-onset (HO) CDI rates were calculated after (1) correcting inaccurate case reporting found during audits, (2) incorporating knowledge of laboratory results from outside hospitals, (3) excluding days when patients were not at risk from the denominator of the rates, and (4) adjusting for patient age. Data sets were simulated with each of these sources of bias reintroduced individually and combined. The simulated rates were compared with the corrected rates. Performance (ie, better, worse, or average compared with the state average) was categorized, and misclassification compared with the corrected data set was measured. RESULTS: Counting days patients were not at risk in the denominator reduced the state HO rate by 45% and resulted in 8% misclassification. Age adjustment and reporting errors also shifted rates (7% and 6% misclassification, respectively). CONCLUSIONS: Changing the NHSN protocol to require reporting of age-stratified patient-days and adjusting for patient-days at risk would improve comparability of rates across hospitals. Further research is needed to validate the risk-adjustment model before these data should be used as hospital performance measures.

Estimating HCV prevalence at the state level: a call to increase and strengthen current surveillance systems.

The degree to which case surveillance captures persons ever infected with HCV is unknown. We determined the discrepancy between HCV seroprevalence, estimated from national survey data, among adults in New York State in 2008 (n = 286 262, or 1.95%) and the number of infected persons reported to the state's surveillance hepatitis registries (n = 144 015). Findings suggest the need to strengthen the existing surveillance system.

Parsimonious conditional-mean model selection with multiple covariates: an analysis of infant mortality in the USA.

This paper proposes and evaluates an objective methodology to select a parsimonious conditional-mean model when faced with multiple candidate predictor variables. The methodology attempts to fine-tune a well-established covariate screening method such as iterative sure independence screening with smoothly clipped absolute deviation penalty by using the following: (i) cross-validated or bootstrap estimates of prediction error; (ii) an objective model comparison strategy; and (iii) multiple hypothesis testing. The methods are analytically and numerically shown to work well in the sense that the probability that the final model selected contains one or more unimportant variables is asymptotically bounded at a preselected level for arbitrary data-generating distributions. This methodology is illustrated with a dataset consisting of birth certificate information and mortality records from year 2001 from the US Department of Health and Human Services on non-Hispanic African American female and male infants. It is shown how the instantaneous daily mortality hazard can be modeled flexibly by allowing both the set of important predictors and their effect on the hazard to change arbitrarily thru time. Results indicate that once controlling for birth weight, no other variables on the birth certificate are significantly associated with mortality; furthermore, time and sex modify the birth weight/survival relationship, with the strongest association at earliest days and low birth weight female infants having a better survival experience than male counterparts.

Racial disparities in infant mortality: what has birth weight got to do with it and how large is it?

BACKGROUND: It has been hypothesized that birth weight is not on the causal pathway to infant mortality, at least among "normal" births (i.e. those located in the central part of the birth weight distribution), and that US racial disparities (African American versus European American) may be underestimated. Here these hypotheses are tested by examining the role of birth weight on racial disparities in infant mortality. METHODS: A two-component Covariate Density Defined mixture of logistic regressions model is used to decompose racial disparities, 1) into disparities due to "normal" versus "compromised" components of the birth cohort, and 2) further decompose these components into indirect effects, which are associated with birth weight, versus direct effects, which are independent of birth weight. RESULTS: The results indicate that a direct effect is responsible for the racial disparity in mortality among "normal" births. No indirect effect of birth weight is observed despite significant disparities in birth weight. Among "compromised" births, an indirect effect is responsible for the disparity, which is consistent with disparities in birth weight. However, there is also a direct effect among "compromised" births that reduces the racial disparity in mortality. This direct effect is responsible for the "pediatric paradox" and maybe due to differential fetal loss. Model-based adjustment for this effect indicates that racial disparities corrected for fetal loss could be as high as 3 or 4 fold. This estimate is higher than the observed racial disparities in infant mortality (2.1 for both sexes). CONCLUSIONS: The results support the hypothesis that birth weight is not on the causal pathway to infant mortality among "normal" births, although birth weight could play a role among "compromised" births. The overall size of the US racial disparities in infant mortality maybe considerably underestimated in the observed data possibly due to racial disparities in fetal loss.

Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment.

BACKGROUND: The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection. METHODS: Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids. RESULTS: Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm. CONCLUSION: Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy: final 48-week clinical and virologic outcomes.

BACKGROUND: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety. METHODS: Subjects with virologic suppression after > or = 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor (PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure (confirmed HIV-1 RNA level > or = 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing (SGS). Residual viremia (1.1-49 copies/mL) was measured by single-copy assay. RESULTS: Thirty-four subjects simplified to ATV/RTV alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS. CONCLUSIONS: In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy.

Flexible regression model selection for survival probabilities: with application to AIDS.

Clinicians are often interested in the effect of covariates on survival probabilities at prespecified study times. Because different factors can be associated with the risk of short- and long-term failure, a flexible modeling strategy is pursued. Given a set of multiple candidate working models, an objective methodology is proposed that aims to construct consistent and asymptotically normal estimators of regression coefficients and average prediction error for each working model, that are free from the nuisance censoring variable. It requires the conditional distribution of censoring given covariates to be modeled. The model selection strategy uses stepup or stepdown multiple hypothesis testing procedures that control either the proportion of false positives or generalized familywise error rate when comparing models based on estimates of average prediction error. The context can actually be cast as a missing data problem, where augmented inverse probability weighted complete case estimators of regression coefficients and prediction error can be used (Tsiatis, 2006, Semiparametric Theory and Missing Data). A simulation study and an interesting analysis of a recent AIDS trial are provided.

Quantifying nonspecific TEM beta-lactamase (blaTEM) genes in a wastewater stream.

To control the antibiotic resistance epidemic, it is necessary to understand the distribution of genetic material encoding antibiotic resistance in the environment and how anthropogenic inputs, such as wastewater, affect this distribution. Approximately two-thirds of antibiotics administered to humans are beta-lactams, for which the predominant bacterial resistance mechanism is hydrolysis by beta-lactamases. Of the beta-lactamases, the TEM family is of overriding significance with regard to diversity, prevalence, and distribution. This paper describes the design of DNA probes universal for all known TEM beta-lactamase genes and the application of a quantitative PCR assay (also known as Taqman) to quantify these genes in environmental samples. The primer set was used to study whether sewage, both treated and untreated, contributes to the spread of these genes in receiving waters. It was found that while modern sewage treatment technologies reduce the concentrations of these antibiotic resistance genes, the ratio of bla(TEM) genes to 16S rRNA genes increases with treatment, suggesting that bacteria harboring bla(TEM) are more likely to survive the treatment process. Thus, beta-lactamase genes are being introduced into the environment in significantly higher concentrations than occur naturally, creating reservoirs of increased resistance potential.

Class-sparing regimens for initial treatment of HIV-1 infection.

BACKGROUND: The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. METHODS: In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups. RESULTS: At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. CONCLUSIONS: Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).

Testing for associations with missing high-dimensional categorical covariates.

Understanding how long-term clinical outcomes relate to short-term response to therapy is an important topic of research with a variety of applications. In HIV, early measures of viral RNA levels are known to be a strong prognostic indicator of future viral load response. However, mutations observed in the high-dimensional viral genotype at an early time point may change this prognosis. Unfortunately, some subjects may not have a viral genetic sequence measured at the early time point, and the sequence may be missing for reasons related to the outcome. Complete-case analyses of missing data are generally biased when the assumption that data are missing completely at random is not met, and methods incorporating multiple imputation may not be well-suited for the analysis of high-dimensional data. We propose a semiparametric multiple testing approach to the problem of identifying associations between potentially missing high-dimensional covariates and response. Following the recent exposition by Tsiatis, unbiased nonparametric summary statistics are constructed by inversely weighting the complete cases according to the conditional probability of being observed, given data that is observed for each subject. Resulting summary statistics will be unbiased under the assumption of missing at random. We illustrate our approach through an application to data from a recent AIDS clinical trial, and demonstrate finite sample properties with simulations.

Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression.

CONTEXT: The long-term adverse effects, expense, and difficulty of adherence to antiretroviral regimens have led to studies of simpler maintenance therapies. Maintenance therapy with ritonavir-boosted atazanavir alone is a possible option because of low pill burden, once-daily dosing, safety, and unique resistance profile. OBJECTIVE: To assess whether simplified maintenance therapy with atazanavir-ritonavir alone after virologic suppression increases the risk of virologic failure (2 consecutive human immunodeficiency virus type 1 [HIV-1] RNA measurements of > or =200 copies/mL). DESIGN, SETTING, AND PARTICIPANTS: Single-group, open-label, multicenter, 24-week pilot study of 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)-based regimen. The study was conducted between September 1, 2004, and April 18, 2006, at 12 participating AIDS clinical trial units in the United States. INTERVENTION: Participants switched PIs to atazanavir-ritonavir at entry and discontinued nucleoside analog reverse transcriptase inhibitors (NRTIs) after 6 weeks. MAIN OUTCOME MEASURES: Virologic failure within 24 weeks of discontinuing NRTIs. Other measures included HIV-1 drug resistance, plasma atazanavir concentrations, adverse events, CD4 cell counts, plasma lipid levels, and HIV-1 RNA levels in seminal plasma. RESULTS: Thirty-six participants enrolled and 2 discontinued before simplification to atazanavir-ritonavir alone. Thirty-four patients were included in the analysis of the primary end point after 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91% (31 of 34 patients; lower 90% confidence interval limit = 85%). Three participants experienced virologic failure 12, 14, and 20 weeks after simplification, with plasma HIV-1 RNA levels of 4730, 1285, and 28 397 copies/mL, respectively. Resistance testing at failure did not identify PI resistance mutations. Plasma atazanavir concentrations at failure were low or below detection in 2 of 3 participants experiencing failure. There were no treatment discontinuations for adverse events after simplification; no significant changes in CD4 cell counts or plasma lipid levels; and no detectable HIV-1 RNA in seminal plasma from all 8 participants tested. CONCLUSIONS: These preliminary data suggest that simplified maintenance therapy with atazanavir-ritonavir alone may be efficacious for maintaining virologic suppression in carefully selected patients with HIV infection. These findings require confirmation in larger, randomized trials of this strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00084019.