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1.  Mycobacterium tuberculosis Antigen 85A Induces Th-1 Immune Responses in Systemic Sarcoidosis 
Journal of clinical immunology  2007;27(4):445-454.
Sarcoidosis is a granulomatous disease of unknown etiology, characterized by a Th-1 immunophenotype. Although humoral immune responses by sarcoidosis subjects to mycobacterial proteins have been detected, mycobacterial antigens capable of inducing cellular immune responses in sarcoidosis subjects have not been reported. We used the enzyme-linked immunospot assay to assess for recognition of the Mycobacterium tuberculosis mycolyl transferase, Antigen 85A, by peripheral blood mononuclear cells from 25 sarcoidosis subjects, 22 PPD− (purified protein derivative) healthy volunteers, and 16 PPD+ healthy subjects. Reactivity to Ag85A whole protein was observed in 15 of 25 sarcoidosis subjects compared to 2 of 22 PPD− subjects (p = 0.0006, Fisher’s exact test) and to 14 of 16 PPD+ subjects (p = 0.084, Fisher’s exact test). Monoclonal antibody against HLA-DR inhibited recognition. In addition to immune recognition of Ag85A whole protein, peptide-mapping studies identified four immunogenic Ag85A peptides, which induced Th-1 immune responses in individual sarcoidosis subjects, suggesting that multiple epitopes from a mycobacterial protein may have a role in sarcoidosis immunopathogenesis.
doi:10.1007/s10875-007-9080-4
PMCID: PMC3962023  PMID: 17357846
Sarcoidosis; mycobacteria; antigen; Th-1 immunophenotype
2.  Self-reported Dietary Intake and Appetite Predict Early Treatment Outcome among Low Body Mass Index Adults Initiating HIV Treatment in sub-Saharan Africa 
Public health nutrition  2012;16(3):549-558.
Objective
Low body mass index (BMI) is a major risk factor for early mortality among HIV infected persons starting antiretrovial therapy (ART) in sub-Saharan Africa, and the common patient belief that antiretroviral medications produce distressing levels of hunger is a barrier to treatment adherence. We assessed relationships between appetite, dietary intake, and treatment outcome 12 weeks after ART initiation among HIV infected adults with advanced malnutrition and immunosuppression.
Design
A prospective, observational cohort study. Dietary intake was assessed using a 24-hour recall survey. The relationships of appetite, intake, and treatment outcome were analyzed using time-varying Cox models.
Setting
A public-sector HIV clinic in Lusaka, Zambia.
Subjects
142 HIV-infected adults starting ART with BMI <16 kg/m2 and/or CD4+ lymphocyte count <50 cells/µl.
Results
Median age, BMI, and CD4+ lymphocyte count were 32 years, 16 kg/m2, and 34 cells/µL, respectively. Twenty-five participants (18%) died before 12 weeks, and another 33 (23%) were lost to care. A 500 kJ/day higher energy intake at any time after ART initiation was associated with an approximate 16% reduction in the hazard of death (AHR 0.84; p=0.01), but the relative contribution of carbohydrate, protein, and fat to total energy was not a significant predictor of outcome. Appetite normalized gradually among survivors, and hunger was rarely reported.
Conclusions
Poor early ART outcomes were strikingly high in a cohort of HIV-infected adults with advanced malnutrition, and mortality was predicted by lower dietary intake. Intervention trials to promote post-ART intake in this population may benefit survival and are warranted.
doi:10.1017/S1368980012002960
PMCID: PMC3772135  PMID: 22691872
HIV; malnutrition; antiretroviral therapy; Africa
3.  Risk Factors for Delayed Initiation of Combination Antiretroviral Therapy in Rural North central Nigeria 
Background
Timely initiation of combination antiretroviral therapy (ART) in eligible HIV-infected patients is associated with substantial reductions in mortality and morbidity. Nigeria has the second largest number of persons living with HIV/AIDS in the world. We examined patient characteristics, time to ART initiation, retention and mortality at five rural facilities in Kwara and Niger states of Nigeria.
Methods
We analyzed program-level cohort data for HIV-infected, ART-naïve clients (≥15 years) enrolled from June 2009-February 2011. We modeled the probability of ART initiation among clients meeting national ART eligibility criteria using logistic regression with splines.
Results
We enrolled 1,948 ART-naïve adults/adolescents into care, of whom 1174 were ART eligible (62% female). Only 74% of eligible patients (n=869) initiated ART within 90 days post-enrollment. The median CD4+ count for eligible clients was 156 cells/μL [IQR: 81–257], with 67% in WHO stage III/IV disease. Adjusting for CD4+ count, WHO stage, functional status, hemoglobin, body mass index, sex, age, education, marital status, employment, clinic of attendance, and month of enrollment, we found that immunosuppression (CD4 350 vs. 200, odds ratio (OR)=2.10 [95%CI: 1.31, 3.35], functional status (bedridden vs. working, OR=4.17 [95%CI: 1.63–10.67]), clinic of attendance (Kuta hospital vs. referent: OR=5.70 [95%CI:2.99–10.89]), and date of enrollment (December 2010 vs. June 2009: OR=2.13 [95%CI:1.19–3.81]) were associated with delayed ART initiation.
Conclusion
Delayed initiation of ART was associated with higher CD4+ counts, lower functional status, clinic of attendance, and later dates of enrollment among ART-eligible clients. Our findings provide targets for quality improvement efforts that may help reduce attrition and improve ART uptake in similar settings.
doi:10.1097/QAI.0b013e31829ceaec
PMCID: PMC3818360  PMID: 23727981
HIV/AIDS; Nigeria; antiretroviral therapy; implementation science; outcomes; PEPFAR; retention; mortality
4.  Active cocaine use is associated with lack of HIV-1 virologic suppression independent of non-adherence to antiretroviral therapy: use of a rapid screening tool during routine clinic visits 
AIDS care  2012;25(1):109-117.
Clarifying the relationship between illicit drug use and HIV-1 virologic suppression requires characterization of both illicit drug use activity and adherence to antiretroviral therapy (ART). We developed a rapid clinical questionnaire to assess prior 7-day illicit drug use and ART adherence in a cross-sectional study among 1,777 HIV-infected persons in care. Of these, 76% were male, 35% were African-American, and 8% reported injection drug use as their probable route of HIV-1 infection. Questionnaire-reported frequencies of cocaine and marijuana use within the previous 7 days were 3.3% and 12.1%, respectively. Over three quarters (77.8%) of participants were on ART, of whom 69.7% had HIV-1 virologic suppression (HIV-1 RNA<48 copies/mL). Univariate analyses revealed that compared to no use, cocaine and marijuana use were both associated with missed ART doses (P<0.01). Multivariable logistic regression analysis adjusting for non-adherence demonstrated that cocaine use was independently associated with failing to achieve virologic suppression (adjusted odds ratio (aOR), 0.46; 95% confidence interval (CI), 0.22–0.98) but marijuana use was not (aOR, 1.08; 95% CI, 0.72–1.62). This result strengthens the evidence of a direct effect of cocaine on virologic control, independent of non-adherence to ART.
doi:10.1080/09540121.2012.687814
PMCID: PMC3443534  PMID: 22670566
Drug use; cocaine; marijuana; antiretroviral therapy; HIV-1 virologic suppression
5.  Sensitivity Analysis of Per-Protocol Time-to-Event Treatment Efficacy in Randomized Clinical Trials 
Journal of the American Statistical Association  2013;108(503):10.1080/01621459.2013.786649.
Summary
Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials. The typical analysis uses the same method employed for the intention-to-treat analysis (e.g., standard survival analysis) applied to the subgroup meeting protocol adherence criteria. However, due to potential post-randomization selection bias, this analysis may mislead about treatment efficacy. Moreover, while there is extensive literature on methods for assessing causal treatment effects in compliers, these methods do not apply to a common class of trials where a) the primary objective compares survival curves, b) it is inconceivable to assign participants to be adherent and event-free before adherence is measured, and c) the exclusion restriction assumption fails to hold. HIV vaccine efficacy trials including the recent RV144 trial exemplify this class, because many primary endpoints (e.g., HIV infections) occur before adherence is measured, and nonadherent subjects who receive some of the planned immunizations may be partially protected. Therefore, we develop methods for assessing per-protocol treatment efficacy for this problem class, considering three causal estimands of interest. Because these estimands are not identifiable from the observable data, we develop nonparametric bounds and semiparametric sensitivity analysis methods that yield estimated ignorance and uncertainty intervals. The methods are applied to RV144.
doi:10.1080/01621459.2013.786649
PMCID: PMC3811958  PMID: 24187408
As-treated; Bounds; Causal inference; Exclusion restriction; Ignorance region; Intention to treat; Principal stratification; Selection bias; Survival analysis
6.  HIV/AIDS-Related Attitudes and Practices Among Traditional Healers in Zambézia Province, Mozambique 
Abstract
Objectives
To document HIV knowledge, treatment practices, and the willingness of traditional healers to engage with the health system in Zambézia Province, Mozambique.
Settings/location
Traditional healers offer culturally acceptable services and are more numerous in Mozambique than are allopathic providers. Late presentation of human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) is reported among persons who have first sought care from traditional healers.
Design
One hundred and thirty-nine (139) traditional healers were interviewed in their native languages (Chuabo or Lomwe) in Zambézia Province. Furthermore, 24 traditional healers were observed during patient encounters. Healers answered a semistructured questionnaire regarding their knowledge of HIV/AIDS, general treatment practices, attitudes toward the allopathic health system, and their beliefs in their abilities to cure AIDS.
Results
Traditional healers were older and had less formal education than the general population. Razor cutting in order to rub herbs into bloodied skin was observed, and healers reported razor cutting as a routine practice. Healers stated that they did not refer HIV patients to clinics for two principal reasons: (1) patient symptoms/signs of HIV were unrecognized, and (2) practitioners believed they could treat the illness effectively themselves. Traditional healers were far more likely to believe in a spiritual than an infectious origin of HIV disease. Prior HIV/AIDS training was not associated with better knowledge or referral practices, though 81% of healers were interested in engaging allopathic providers.
Conclusions
It was found that the HIV-related practices of traditional healers probably increase risk for both HIV-infected and uninfected persons through delayed care and reuse of razors. Mozambican traditional healers attribute HIV pathogenesis to spiritual, not infectious, etiologies. Healers who had received prior HIV training were no more knowledgeable, nor did they have better practices. The willingness expressed by 4 in 5 healers to engage local formal health providers in HIV/AIDS care suggests a productive way forward, though educational efforts must be effective and income concerns considered.
doi:10.1089/acm.2011.0682
PMCID: PMC3513988  PMID: 23171035
7.  Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics 
Background HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear.
Methods We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression.
Results During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts’ estimated completeness of death ascertainment [excellent: 96–100%, good: 90–95%, average: 75–89%; mortality rate ratio 0.66 (95% confidence interval 0.46–0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31–0.57) before and 0.47 (0.30–0.73) after adjusting for completeness of ascertainment.
Conclusions Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk.
doi:10.1093/ije/dys164
PMCID: PMC3535877  PMID: 23148105
HIV; AIDS; antiretroviral therapy; mortality; cohort; heterogeneity; prognostic model; socio-economic status
8.  Using Audit Information to Adjust Parameter Estimates for Data Errors in Clinical Trials 
Background
Audits are often performed to assess the quality of clinical trial data, but beyond detecting fraud or sloppiness, the audit data is generally ignored. In earlier work using data from a non-randomized study, Shepherd and Yu (2011) developed statistical methods to incorporate audit results into study estimates, and demonstrated that audit data could be used to eliminate bias.
Purpose
In this manuscript we examine the usefulness of audit-based error-correction methods in clinical trial settings where a continuous outcome is of primary interest.
Methods
We demonstrate the bias of multiple linear regression estimates in general settings with an outcome that may have errors and a set of covariates for which some may have errors and others, including treatment assignment, are recorded correctly for all subjects. We study this bias under different assumptions including independence between treatment assignment, covariates, and data errors (conceivable in a double-blinded randomized trial) and independence between treatment assignment and covariates but not data errors (possible in an unblinded randomized trial). We review moment-based estimators to incorporate the audit data and propose new multiple imputation estimators. The performance of estimators is studied in simulations.
Results
When treatment is randomized and unrelated to data errors, estimates of the treatment effect using the original error-prone data (i.e., ignoring the audit results) are unbiased. In this setting, both moment and multiple imputation estimators incorporating audit data are more variable than standard analyses using the original data. In contrast, in settings where treatment is randomized but correlated with data errors and in settings where treatment is not randomized, standard treatment effect estimates will be biased. And in all settings, parameter estimates for the original, error-prone covariates will be biased. Treatment and covariate effect estimates can be corrected by incorporating audit data using either the multiple imputation or moment-based approaches. Bias, precision, and coverage of confidence intervals improve as the audit size increases.
Limitations
The extent of bias and the performance of methods depend on the extent and nature of the error as well as the size of the audit. This work only considers methods for the linear model. Settings much different than those considered here need further study.
Conclusions
In randomized trials with continuous outcomes and treatment assignment independent of data errors, standard analyses of treatment effects will be unbiased and are recommended. However, if treatment assignment is correlated with data errors or other covariates, naive analyses may be biased. In these settings, and when covariate effects are of interest, approaches for incorporating audit results should be considered.
doi:10.1177/1740774512450100
PMCID: PMC3728661  PMID: 22848072
audit; bias; clinical trials; measurement error; multiple imputation
9.  Estimating the Optimal CD4 Count for HIV-infected Persons to Start Antiretroviral Therapy 
Epidemiology (Cambridge, Mass.)  2010;21(5):698-705.
Background
Optimal timing of antiretroviral therapy in HIV-infected persons is unclear, although two recent large observational studies have improved our understanding of the best CD4 threshold for initiation. These studies compared the effect of starting HAART on mortality and mortality/AIDS between strata defined using broad ranges of CD4 counts. We sought to expand this understanding using a novel statistical approach proposed by Robins and colleagues.
Methods
Using observational data from 1034 antiretroviral-naïve HIV-infected patients from Nashville, Tennessee, we directly estimated the optimal CD4 count for initiation of HAART to maximize patient health 6, 12, 24, and 36 months after the first instance of CD4 falling below 750. We measured health using two outcome metrics, one based on CD4 counts at the end of follow-up and the other based on a published quality-of-life scale; both metrics incorporated death, AIDS-defining events, serious non-AIDS events, and CD4 at the end of follow-up if asymptomatic.
Results
The CD4-based metric estimated that to maximize health 6, 12, 24, and 36 months after study entry, HAART should be initiated within 3 months of CD4 first dropping below 495 (95% confidence interval [CI] = 468 – 522), 554 (459 – 750), 489 (427 – 750), and 509 (460 – 750), respectively. The quality-of-life-based metric produced CD4 initiation threshold estimates of 337 (95% CI = 201–442), 354 (288 – 386), 358 (294 – 750), and 475 (287 – 750) for the same time points.
Conclusions
Our results support early initiation of antiretroviral therapy, although the criterion for starting therapy depends on the choice of health outcome.
doi:10.1097/EDE.0b013e3181e97737
PMCID: PMC3086582  PMID: 20585252
10.  Utilization of Cervical Cancer Screening Services and Trends in Screening Positivity Rates in a ‘Screen-And-Treat’ Program Integrated with HIV/AIDS Care in Zambia 
PLoS ONE  2013;8(9):e74607.
Background
In the absence of stand-alone infrastructures for delivering cervical cancer screening services, efforts are underway in sub-Saharan Africa to dovetail screening with ongoing vertical health initiatives like HIV/AIDS care programs. Yet, evidence demonstrating the utilization of cervical cancer prevention services in such integrated programs by women of the general population is lacking.
Methods
We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia (CCPPZ), the largest public sector programs of its kind in sub-Saharan Africa. We evaluated patterns of utilization of screening services by HIV serostatus, examined contemporaneous trends in screening outcomes, and used multivariable modeling to identify factors associated with screening test positivity.
Results
Between January 2006 and April 2011, CCPPZ services were utilized by 56,247 women who underwent cervical cancer screening with visual inspection with acetic acid (VIA), aided by digital cervicography. The proportion of women accessing these services who were HIV-seropositive declined from 54% to 23% between 2006–2010, which coincided with increasing proportions of HIV-seronegative women (from 22% to 38%) and women whose HIV serostatus was unknown (from 24% to 39%) (all p-for trend<0.001). The rates of VIA screening positivity declined from 47% to 17% during the same period (p-for trend <0.001), and this decline was consistent across all HIV serostatus categories. After adjusting for demographic and sexual/reproductive factors, HIV-seropositive women were more than twice as likely (Odds ratio 2.62, 95% CI 2.49, 2.76) to screen VIA-positive than HIV-seronegative women.
Conclusions
This is the first ‘real world’ demonstration in a public sector implementation program in a sub-Saharan African setting that with successful program scale-up efforts, nurse-led cervical cancer screening programs targeting women with HIV can expand and serve all women, regardless of HIV serostatus. Screening program performance can improve with adequate emphasis on training, quality control, and telemedicine-support for nurse-providers in clinical decision making.
doi:10.1371/journal.pone.0074607
PMCID: PMC3776830  PMID: 24058599
11.  Duration of Anti-Tuberculosis Therapy and Timing of Antiretroviral Therapy Initiation: Association with Mortality in HIV-Related Tuberculosis 
PLoS ONE  2013;8(9):e74057.
Background
Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear.
Methods
We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended.
Results
Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm3, 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti-tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007).
Conclusions
The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated.
doi:10.1371/journal.pone.0074057
PMCID: PMC3774609  PMID: 24066096
12.  Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial 
Abstract
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08–1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1–1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03–3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.
doi:10.1089/aid.2011.0303
PMCID: PMC3399551  PMID: 22540188
13.  A new residual for ordinal outcomes 
Biometrika  2012;99(2):473-480.
We propose a new residual for regression models of ordinal outcomes, defined as E{sign(y,Y)}, where y is the observed outcome and Y is a random variable from the fitted distribution. This new residual is a single value per subject irrespective of the number of categories of the ordinal outcome, contains directional information between the observed value and the fitted distribution, and does not require the assignment of arbitrary numbers to categories. We study its properties, describe its connections with other residuals, ranks and ridits, and demonstrate its use in model diagnostics.
doi:10.1093/biomet/asr073
PMCID: PMC3635659  PMID: 23843667
Model diagnostics; Ordinal outcome; Ordinal regression; Residual
14.  Serum Phosphate Predicts Early Mortality among Underweight Adults Starting ART in Zambia: A Novel Context for Refeeding Syndrome? 
Background. Low body mass index (BMI) at antiretroviral therapy (ART) initiation is associated with early mortality, but the etiology is not well understood. We hypothesized that low pretreatment serum phosphate, a critical cellular metabolism intermediate primarily stored in skeletal muscle, may predict mortality within the first 12 weeks of ART. Methods. We prospectively studied 352 HIV-infected adults initiating ART in Lusaka, Zambia to estimate the odds of death for each 0.1 mmol/L decrease in baseline phosphate after adjusting for established predictors of mortality. Results. The distribution of phosphate values was similar across BMI categories (median value 1.2 mmol/L). Among the 145 participants with BMI <18.5 kg/m2, 28 (19%) died within 12 weeks. Lower pretreatment serum phosphate was associated with increased mortality (odds ratio (OR) 1.24 per 0.1 mmol/L decrement, 95% CI: 1.05 to 1.47; P = 0.01) after adjusting for sex, age, and CD4+ lymphocyte count. A similar relationship was not observed among participants with BMI ≥18.5 kg/m2 (OR 0.96, 95% CI: 0.76 to 1.21; P = 0.74). Conclusions. The association of low pretreatment serum phosphate level and early ART mortality among undernourished individuals may represent a variant of the refeeding syndrome. Further studies of cellular metabolism in this population are needed.
doi:10.1155/2013/545439
PMCID: PMC3652146  PMID: 23691292
15.  A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses 
Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear.
Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing.
Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma.
Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21–2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ1, children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57–2.46; P = 0.66).
Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ1 responses mediate exacerbations caused by HRV. Modulation of IFN- λ1 should be studied as a therapeutic target for exacerbations caused by HRV.
doi:10.1164/rccm.201108-1462OC
PMCID: PMC3361761  PMID: 22135341
asthma; interferon-λ; rhinovirus; children; asthma exacerbation
16.  Human Rhinoviruses in Severe Respiratory Disease in Very Low Birth Weight Infants 
Pediatrics  2012;129(1):e60-e67.
Objectives:
To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants.
Methods:
A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction.
Results:
Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed.
Conclusions:
HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants.
doi:10.1542/peds.2011-0583
PMCID: PMC3255465  PMID: 22201153
premature infants; rhinovirus; very low birth weight
17.  Dual Analysis for Mycobacteria and Propionibacteria in Sarcoidosis BAL 
Journal of clinical immunology  2012;32(5):1129-1140.
Purpose
Sarcoidosis is a non-caseating granulomatous disease for which a role for infectious antigens continues to strengthen. Recent studies have reported molecular evidence of mycobacteria or propionibacteria. We assessed for immune responses against mycobacterial and propionibacterial antigens in sarcoidosis bronchoalveolar lavage (BAL) using flow cytometry, and localized signals consistent with microbial antigens with sarcoidosis specimens, using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS).
Methods
BAL cells from 27 sarcoidosis, 14 PPD- controls, and 9 subjects with nontuberculosis mycobacterial (NTM) infections were analyzed for production of IFN-γ after stimulation with mycobacterial ESAT-6 and Propionibacterium acnes proteins. To complement the immunological data, MALDI-IMS was performed to localize ESAT-6 and Propionibacterium acnes signals within sarcoidosis and control specimens.
Results
CD4+ immunologic analysis for mycobacteria was positive in 17/27 sarcoidosis subjects, compared to 2/14 PPD-subjects, and 5/9 NTM subjects (p=00.008 and p=00.71 respectively, Fisher's exact test). There was no significant difference for recognition of P. acnes, which occurred only in sarcoidosis subjects that also recognized ESAT-6. Similar results were also observed for the CD8+ immunologic analysis. MALDI-IMS localized signals consistent with ESAT-6 only within sites of granulomatous inflammation, whereas P. acnes signals were distributed throughout the specimen.
Conclusions
MALDI-IMS localizes signals consistent with ESAT-6 to sarcoidosis granulomas, whereas no specific localization of P. acnes signals is detected. Immune responses against both mycobacterial and P. acnes are present within sarcoidosis BAL, but only mycobacterial signals are distinct from disease controls. These immunologic and molecular investigations support further investigation of the microbial community within sarcoidosis granulomas.
doi:10.1007/s10875-012-9700-5
PMCID: PMC3526106  PMID: 22552860
Sarcoidosis; mycobacteria; propionibacteria; bronchoalveolar lavage; mass spectrometry; MALDI-IMS
18.  Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India 
Human immunodeficiency virus (HIV)-infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)-induced cervical cancer remains unabated because of lack of cost-effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV-infected women. We evaluated 303 nonpregnant HIV-infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low-grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high-grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV-positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 µL−1. Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV-infected women. Implementing VIA-based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low-cost HPV-based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.
doi:10.1002/ijc.25971
PMCID: PMC3516675  PMID: 21387289
cervical cancer; visual inspection; cytology; screening; HIV/AIDS; India
19.  An Optimal Body Mass Index Range Associated With Improved Immune Reconstitution Among HIV-Infected Adults Initiating Antiretroviral Therapy 
In a cohort of human immunodeficiency virus–infected adults beginning antiretroviral therapy, CD4+ lymphocyte recovery at 12 months was highest among overweight patients (body mass index, 25–30 kg/m2). Similar results were observed in the subgroups with virologic suppression and minimal weight change.
Background. Higher body mass index (BMI) was associated with slower human immunodeficiency virus (HIV) disease progression before the availability of effective antiretroviral therapy (ART), but the relationship between pretreatment BMI and CD4+ lymphocyte recovery on ART is not well described.
Methods. We conducted an observational cohort study of HIV-infected, ART-naive adults starting treatment at a clinic affiliated with Vanderbilt University in Nashville, Tennessee. We assessed the relationship between pretreatment BMI and CD4+ lymphocyte count change from baseline to 12 months in all subjects, among those with plasma HIV-1 RNA levels <400 copies/mL for ≥6 months and those with <10% change in weight during follow-up. Linear regression models were adjusted for age, sex, race, protease inhibitor usage, year of ART initiation, and baseline CD4+ lymphocyte count and HIV-1 RNA level.
Results. A total of 915 patients met inclusion criteria; 78% were male, and their median age, BMI, and CD4+ lymphocyte count were 39 years, 24 kg/m2, and 171 cells/μL, respectively. The CD4+ lymphocyte increase at 12 months was greatest among patients with a pretreatment BMI of ∼25–30 kg/m2 and diminished above and below this range (P = .03). Similar patterns were observed in the subgroup analyses. Among patients with a pretreatment CD4+ lymphocyte count <200 cells/μL, a BMI of ∼25 kg/m2 was associated with the highest odds of reaching a CD4+ lymphocyte count >350 cells/μL at 12 months (P = .05).
Conclusions. 12-month immune reconstitution on ART was highest among patients commonly classified as overweight, suggesting there may be an optimal BMI range for immune recovery on ART.
doi:10.1093/cid/cir606
PMCID: PMC3189168  PMID: 21946189
20.  Hemoglobin May Contribute to Sex Differences in Mortality among HIV-Infected Persons in Care 
PLoS ONE  2012;7(9):e44999.
Background
Some retrospective studies have found that HIV-infected women have a higher mortality risk than men after adjusting for baseline characteristics, while others have not. Anemia is a known predictor of HIV-related mortality. We assessed whether anemia contributed to the sex difference in mortality in our cohort.
Methods
We conducted a retrospective cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between 1998 and 2009. Cox proportional hazards models compared time from first clinic visit to death and AIDS-defining events (ADE), adjusted for baseline characteristics with and without baseline hemoglobin.
Results
Of 3,633 persons, 879 (24%) were women. Women had lower median baseline hemoglobin compared to men: 12.4 g/dL (inter-quartile range (IQR) 11.3–13.4) vs. 14.4 (IQR 13.1–15.5), respectively (P<0.001). In multivariable models without hemoglobin, the risk of death was higher among women: hazard ratio (HR) 1.46 (95% confidence interval (CI) 1.17, 1.82; P = 0.001). In multivariable models with hemoglobin, the risk of death in women was diminished and no longer statistically significant: HR 1.2 (95% CI 0.93, 1.55; P = 0.17). The risk of ADE was higher among women in both models, but not statistically significant: HR 1.1 (95% CI 0.85–1.42; P = 0.46) in the model without hemoglobin and 1.11 (95% CI 0.82–1.48; P = 0.50) in the model with hemoglobin. Hemoglobin was a strong predictor of death: HR 0.88 per 1 g/dL increase (95% CI 0.83, 0.93; P<0.001).
Conclusion
In our study population of HIV-infected persons in care, women had lower baseline hemoglobin, and lower hemoglobin contributed to their higher risk of ADE and death.
doi:10.1371/journal.pone.0044999
PMCID: PMC3441736  PMID: 23028732
21.  Accounting for Data Errors Discovered from an Audit in Multiple Linear Regression 
Biometrics  2011;67(3):1083-1091.
Summary
A data coordinating team performed on-site audits and discovered discrepancies between the data sent to the coordinating center and that recorded at sites. We present statistical methods for incorporating audit results into analyses. This can be thought of as a measurement error problem, where the distribution of errors is a mixture with a point mass at 0. If the error rate is non-zero, then even if the mean of the discrepancy between the reported and correct values of a predictor is 0, naive estimates of the association between two continuous variables will be biased. We consider scenarios where there are 1) errors in the predictor, 2) errors in the outcome, and 3) possibly correlated errors in the predictor and outcome. We show how to incorporate the error rate and magnitude, estimated from a random subset (the audited records), to compute unbiased estimates of association and proper confidence intervals. We then extend these results to multiple linear regression where multiple covariates may be incorrect in the database and the rate and magnitude of the errors may depend on study site. We study the finite sample properties of our estimators using simulations, discuss some practical considerations, and illustrate our methods with data from 2815 HIV-infected patients in Latin America, of whom 234 had their data audited using a sequential auditing plan.
doi:10.1111/j.1541-0420.2010.01543.x
PMCID: PMC3092800  PMID: 21281274
Data quality; HIV/AIDS; Measurement error
22.  Sensitivity Analyses Comparing Time-to-Event Outcomes Only Existing in a Subset Selected Postrandomization and Relaxing Monotonicity 
Biometrics  2010;67(3):1100-1110.
Summary
In randomized studies researchers may be interested in the effect of treatment assignment on a time-to-event outcome that only exists in a subset selected after randomization. For example, in preventative HIV vaccine trials, it is of interest to determine whether randomization to vaccine affects the time from infection diagnosis until initiation of antiretroviral therapy. Earlier work assessed the effect of treatment on outcome among the principal stratum of individuals who would have been selected regardless of treatment assignment. These studies assumed monotonicity, that one of the principal strata was empty (eg, every person infected in the vaccine arm would have been infected if randomized to placebo). Here we present a sensitivity analysis approach for relaxing monotonicity with a time-to-event outcome. We also consider scenarios where selection is unknown for some subjects because of non-informative censoring (e.g., infection status k years after randomization is unknown for some because of staggered study entry). We illustrate our method using data from an HIV vaccine trial.
doi:10.1111/j.1541-0420.2010.01508.x
PMCID: PMC3116075  PMID: 21114663
Causal inference; HIV; Kaplan-Meier; Monotonicity; Principal stratification
23.  The Relationships between Injection and Non-injection Drug Use and HIV Disease Progression 
Background
Injection drug use is associated with poor HIV outcomes even among persons receiving highly active antiretroviral therapy (HAART), but there are limited data on the relationship between non-injection drug use and HIV disease progression.
Methods
We conducted an observational study of HIV-infected persons entering care between January 1, 1999 and December 31, 2004, with follow-up through December 31, 2005.
Results
There were 1,712 persons in the study cohort: 262 with a history of injection drug use (IDU), 785 with a history of non-injection drug use, and 665 with no history of drug use; 56% were white, and 24% were females. Median follow-up was 2.1 years, 33% had HAART prior to first visit, 40% initiated first HAART during the study period, and 306 (17.9%) had an AIDS-defining event or died. Adjusting for sex, age, race, prior antiretroviral use, CD4 cell count, and HIV-1 RNA, patients with a history of injection drug use were more likely to advance to AIDS or death than non-users (adjusted hazard ratio (HR) = 1.97, 95% confidence interval (CI) 1.43-2.70, P<0.01). There was no statistically significant difference of disease progression between non-injection drug users and non-users (HR=1.19, 95% CI 0.92-1.56, P=0.19). An analysis among the subgroup who initiated their first HAART during the study period (n=687) showed a similar pattern (IDUs: 1.83, 1.09-3.06, P=0.02; non-IDUs: 1.21, 0.81-1.80, P=0.35). Seventy-four patients had active IDU during the study period, 768 active non-IDU, and 870 no substance use. Analyses based on active drug use during the study period did not substantially differ from those based on history of drug use.
Conclusions
This study shows no relationship between non-injection drug use and HIV disease progression. This study is limited by using history drug use and lumping together different types of drugs. Further studies ascertaining specific type and extent of non-injection drug use in a prospective way, and with longer follow-up, are needed.
doi:10.1016/j.jsat.2011.01.007
PMCID: PMC3110534  PMID: 21349679
Injection drug use; non-injection drug use; CD4 cell count; HIV viral load; HIV disease progression; antiretroviral therapy
24.  Cancer in HIV-infected Persons from the Caribbean, Central and South America 
Background
HIV infected individuals have heightened cancer risk. With the advent of HAART, the frequency of some AIDS defining cancers (ADC) has decreased while certain non-AIDS defining cancers (NADC) are becoming more frequent. Cancers among HIV-infected individuals in Latin American and the Caribbean have not yet been carefully studied.
Methods
Cancer cases among the Caribbean, Central and South American network for HIV Research (CCASAnet) cohort were identified reviewing clinical records and preexisting databases.
Results
There were 406 cancers reported: 331 ADC (224 Kaposi´s sarcomas and 98 non Hodgkin lymphomas). Most frequent NADC (n=75) were Hodgkin lymphoma and skin cancers. Seventy-three percent of NADC and 45% of ADC were diagnosed >1 year after HIV diagnosis. 56% of ADC occurred before HAART start. Median time from HAART start until cancer diagnosis was 2.5 years for NADC and 0.5 years for ADC (p=<0.001). Within 3372 HAART starters, 158 were diagnosed with 165 cancers (82.4% ADC); 85 cases were previous to or concomitant with HAART initiation. Incidence of cancer after HAART initiation in 8080 person-years of follow-up was 7.2 per 1000 person-years (95%CI= 5.5–9.3) for ADC and 2.7 (95%CI= 1.8–4.1) for NADC; incidence was higher in the first two months, particularly for ADC (47.6). A pre-HAART ADC was a predictor of mortality after adjusting for age, sex, and CD4 at HAART initiation.
Conclusions
ADC were the most frequent cancers in this region and were often diagnosed close to HIV diagnosis and HAART start. Incidence of cancer was highest around HAART initiation.
doi:10.1097/QAI.0b013e31820bb1c3
PMCID: PMC3293455  PMID: 21239992
Neoplasms; HIV; Latin America; Caribbean; Cohort Studies
25.  Measuring the Quality of Observational Study Data in an International HIV Research Network 
PLoS ONE  2012;7(4):e33908.
Observational studies of health conditions and outcomes often combine clinical care data from many sites without explicitly assessing the accuracy and completeness of these data. In order to improve the quality of data in an international multi-site observational cohort of HIV-infected patients, the authors conducted on-site, Good Clinical Practice-based audits of the clinical care datasets submitted by participating HIV clinics. Discrepancies between data submitted for research and data in the clinical records were categorized using the audit codes published by the European Organization for the Research and Treatment of Cancer. Five of seven sites had error rates >10% in key study variables, notably laboratory data, weight measurements, and antiretroviral medications. All sites had significant discrepancies in medication start and stop dates. Clinical care data, particularly antiretroviral regimens and associated dates, are prone to substantial error. Verifying data against source documents through audits will improve the quality of databases and research and can be a technique for retraining staff responsible for clinical data collection. The authors recommend that all participants in observational cohorts use data audits to assess and improve the quality of data and to guide future data collection and abstraction efforts at the point of care.
doi:10.1371/journal.pone.0033908
PMCID: PMC3320898  PMID: 22493676

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