Alison G. Abraham

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; P<0.001). 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; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Invasive cervical cancer risk among HIV-infected women: a North American multicohort collaboration prospective study.

Objective:HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection—the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women. Methods:Data were obtained from HIV-infected and -uninfected female participants in the North American AIDS Cohort Collaboration on Research and Design with no history of ICC at enrollment. Participants were followed from study entry or January 1996 through ICC, loss to follow-up, or December 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios. All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction. Results:A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 person-years, respectively). HIV-infected women with baseline CD4+ T-cells of ≥350, 200–349, and <200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in ICC incidence, respectively, compared with HIV-uninfected women (Ptrend = 0.001). Of the 17 HIV-infected women, medical records for the 5 years before diagnosis showed that 6 had no documented screening, 5 had screening with low-grade or normal results, and 6 had high-grade results. Conclusions:This study found elevated incidence of ICC in HIV-infected compared with -uninfected women, and these rates increased with immunosuppression.

Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample. RESULTS CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m(2). Compared with those with a GFR ≥ 50 ml/min per 1.73 m(2), having a GFR < 30 ml/min per 1.73 m(2) was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was -4.3 ml/min per 1.73 m(2) and -1.5 ml/min per 1.73 m(2) per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms. CONCLUSIONS Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m(2) in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR.

Predictors of Rapid Progression of Glomerular and Nonglomerular Kidney Disease in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort

BACKGROUND Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. STUDY DESIGN Prospective multicenter observational cohort study. SETTING & PARTICIPANTS 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. PREDICTORS Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. OUTCOMES Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). RESULTS 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. LIMITATIONS Small number of events in glomerular patients and use of internal cross-validation. CONCLUSIONS Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.

End-Stage Renal Disease Among HIV-Infected Adults in North America

BACKGROUND Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks. METHODS Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18-80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD. RESULTS HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8-3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9-5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection. CONCLUSIONS The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.

Disparities in the Quality of HIV Care When Using US Department of Health and Human Services Indicators

We estimated US Department of Health and Human Services (DHHS)-approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.

FungiQuant: A broad-coverage fungal quantitative real-time PCR assay

BackgroundFungal load quantification is a critical component of fungal community analyses. Limitation of current approaches for quantifying the fungal component in the human microbiome suggests the need for new broad-coverage techniques.MethodsWe analyzed 2,085 18S rRNA gene sequences from the SILVA database for assay design. We generated and quantified plasmid standards using a qPCR-based approach. We evaluated assay coverage against 4,968 sequences and performed assay validation following the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines.ResultsWe designed FungiQuant, a TaqMan® qPCR assay targeting a 351 bp region in the fungal 18S rRNA gene. Our in silico analysis showed that FungiQuant is a perfect sequence match to 90.0% of the 2,617 fungal species analyzed. We showed that FungiQuant’s is 100% sensitive and its amplification efficiencies ranged from 76.3% to 114.5%, with r2-values of >0.99 against the 69 fungal species tested. Additionally, FungiQuant inter- and intra-run coefficients of variance ranged from <10% and <20%, respectively. We further showed that FungiQuant has a limit of quantification 25 copies and a limit of detection at 5 copies. Lastly, by comparing results from human-only background DNA with low-level fungal DNA, we showed that amplification in two or three of a FungiQuant performed in triplicate is statistically significant for true positive fungal detection.ConclusionsFungiQuant has comprehensive coverage against diverse fungi and is a robust quantification and detection tool for delineating between true fungal detection and non-target human DNA.

Staphylococcus aureus and the ecology of the nasal microbiome

Nasal turf wars may provide the secrets to stopping staph. The human microbiome can play a key role in host susceptibility to pathogens, including in the nasal cavity, a site favored by Staphylococcus aureus. However, what determines our resident nasal microbiota—the host or the environment—and can interactions among nasal bacteria determine S. aureus colonization? Our study of 46 monozygotic and 43 dizygotic twin pairs revealed that nasal microbiota is an environmentally derived trait, but the host’s sex and genetics significantly influence nasal bacterial density. Although specific taxa, including lactic acid bacteria, can determine S. aureus colonization, their negative interactions depend on thresholds of absolute abundance. These findings demonstrate that nasal microbiota is not fixed by host genetics and opens the possibility that nasal microbiota may be manipulated to prevent or eliminate S. aureus colonization.

Impact of age on retention in care and viral suppression

Background:Retention in care is important for all HIV-infected persons and is strongly associated with initiation of antiretroviral therapy and viral suppression. However, it is unclear how retention in care and age interact to affect viral suppression. We evaluated whether the association between retention and viral suppression differed by age at entry into care. Methods:Cross-sectional analysis (2006–2010) involving 17,044 HIV-infected adults in 14 clinical cohorts across the United States and Canada. Patients contributed 1 year of data during their first full-calendar year of clinical observation. Poisson regression examined associations between retention measures [US National HIV/AIDS Strategy (NHAS), US Department of Health and Human Services (DHHS), 6-month gap, and 3-month visit constancy] and viral suppression (HIV RNA ⩽200 copies/mL) by age group: 18–29 years, 30–39 years, 40–49 years, 50–59 years, and 60 years or older. Results:Overall, 89% of patients were retained in care using the NHAS measure, 74% with the DHHS indicator, 85% did not have a 6-month gap, and 62% had visits in 3–4 quarters of the year; 54% achieved viral suppression. For each retention measure, the association with viral suppression was significant for only the younger age groups (18–29 and 30–39 years): 18–29 years [adjusted prevalence ratio (APR) = 1.33, 95% confidence interval (CI): 1.03 to 1.70]; 30–39 years (APR = 1.23, 95% CI: 1.01 to 1.49); 40–49 years (APR = 1.06, 95% CI: 0.90 to 1.22); 50–59 (APR = 0.92, 95% CI: 0.75 to 1.13); ≥60 years (APR = 0.99, 95% CI: 0.63 to 1.56) using the NHAS measure as a representative example. Conclusions:These results have important implications for improving viral control among younger adults, emphasizing the crucial role retention in care plays in supporting viral suppression in this population.

Urinary markers of kidney injury and kidney function decline in HIV-infected women.

Objective:HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women. Methods:In the Womens Interagency HIV Study, we measured concentrations of albumin-to-creatinine ratio, interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin from stored urine among 908 HIV-infected and 289 HIV-uninfected participants. Primary analyses used cystatin C-based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and 2 follow-up visits over 8 years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes. Results:Compared with the lowest tertiles, the highest tertiles of albumin-to-creatinine ratio (−0.15 mL/min per 1.73 m2, P < 0.0001), IL-18 (−0.09 mL/min per 1.73 m2, P < 0.0001) and KIM-1 (−0.06 mL/min per 1.73 m2, P < 0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all 3 biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (relative risk = 1.40; 95% confidence interval: 1.04 to 1.89); ≥5% (1.88; 1.30 to 2.71); and ≥10% (2.16; 1.20 to 3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25 to 2.33) and 10% (1.78; 1.07 to 2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00 to 3.87). Conclusions:Among HIV-infected women in the Womens Interagency HIV Study cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.