Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs). METHODS: This cohort study used US health insurance data spanning the years 2008-2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs). RESULTS: We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD -3.96; 95% CI: -7.31, -1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD -3.85; 95% CI: -5.02, -2.78). CONCLUSIONS: In this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower or similar to those for all HIV patients, with the lowest IRs observed among patients receiving EFV/FTC/TDF. Compared with all HIV patients, the observed IR for fracture was higher with EVG/COBI/FTC/TDF, comparable with RPV/FTC/TDF, and lower with EFV/FTC/TDF.

Risk of cardiovascular events among patients with HIV treated with atazanavir-containing regimens: a retrospective cohort study.

BACKGROUND: A previous cohort study indicated that atazanavir (ATV), a protease inhibitor used for HIV treatment, is not associated with an increased risk of cardiovascular (CV) events. The objective of this study was to compare the risk of CV events among antiretroviral-naïve patients initiating ATV-containing versus ATV-free ARV regimens. METHODS: Patients with HIV who newly initiated antiretroviral therapy were selected from MarketScan Commercial and Multi-State Medicaid databases. The first claim for an antiretroviral medication between 1/1/2007 and 12/31/2013 was known as the index date. Patients were categorized as initiating an ATV-containing or an ATV-free regimen. Patients who did not have 6 months of continuous enrollment prior to the index date or who had evidence of a CV event during this time period were excluded. Myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass graft were identified through diagnosis and procedure codes. Patients were followed from index date until a CV event, continuous gap of >30 days without initiated ARV, a claim for ATV in the ATV-free cohort, disenrollment, or study end, whichever occurred first. Unadjusted incidence rates (IR) were calculated and propensity-score-weighted Cox proportional hazards models were fit to compare hazards of CV events between the two cohorts. RESULTS: A total of 22,211 patients (2437 ATV-containing and 19,774 ATV-free) were identified in the Commercial Database and 7136 patients were identified (1505 ATV-containing and 5631 ATV-free) in the Medicaid Database. CV events were uncommon (Commercial IR per 1000 person-years for a CV event: ATV-containing = 3.01, ATV-free = 3.26; Medicaid IR: ATV-containing = 10.9, ATV-free = 9.9). In propensity-score-weighted models combining the two populations, there was no significant difference in the hazards of a CV event for patients initiating an ATV-containing regimen compared with those initiating an ATV-free regimen (hazard ratio = 1.16, 95 % confidence interval 0.67-1.99). CONCLUSIONS: In this real-world analysis, there was no significant increase in the risk of CV events associated with exposure to ATV-containing regimens.

Risk of Cardiovascular Events Among Patients Initiating Efavirenz-Containing Versus Efavirenz-Free Antiretroviral Regimens.

Background. Efavirenz (EFV), an antiretroviral medication used to treat human immunodeficiency virus (HIV) infection, can increase lipid levels. Because hyperlipidemia is associated with increased risk for cardiovascular (CV) events, this study compared the risk of CV events in patients initiating EFV-containing vs EFV-free antiretroviral regimens. Methods. Antiretroviral-naive HIV-positive (HIV+) patients ages 18-64 were selected from commercial and Medicaid insurance claims databases. Patients with ≥1 claim for antiretroviral medications between January 1, 2007 and December 31, 2013 were classified into 2 cohorts: EFV-containing or EFV-free regimens. Patients were required to have 6 months of continuous enrollment before initiation, with no evidence of a CV event during this time. Patients were observed from initiation until the occurrence of a CV event, disenrollment, or study end. Cardiovascular events were identified through diagnosis or procedure codes for myocardial infarction, stroke, percutaneous coronary intervention, or coronary artery bypass graft. We calculated unadjusted incidence rates (IRs) and fit propensity-score-weighted Cox proportional hazards models. Results. There were 22 212 patients (11 978 EFV-containing and 10 234 EFV-free) identified in the commercial database and 7400 patients identified (2943 EFV-containing and 4457 EFV-free) in the Medicaid database. Cardiovascular events were rare (commercial IR = 396 per 100 000 person-years; Medicaid IR = 973 per 100 000 person-years). In propensity-score-weighted models, hazards of CV events were significantly lower for EFV-containing regimens in the commercial database (hazard ratio [HR] = 0.68; 95% confidence interval [CI], .49-.93) No significant difference was found in the Medicaid database (HR = 0.83; 95% CI, .58-1.19). Conclusions. This analysis found no evidence of increased risk of CV events among HIV+ patients initiating EFV-containing regimens.

No Evidence of an Association Between Efavirenz Exposure and Suicidality Among HIV Patients Initiating Antiretroviral Therapy in a Retrospective Cohort Study of Real World Data.

Recently, published studies have reported conflicting results regarding the association between efavirenz exposure and the risk of suicidality among patients with human immunodeficiency virus. The objective of this analysis was to compare the rate of suicidality among patients initiating efavirenz-containing versus efavirenz-free antiretroviral (ARV) regimens.This retrospective cohort study used US administrative claims data for commercially and Medicaid-insured individuals for the years 2006 to 2013. ARV-naive patients aged ≥12 years initiating an efavirenz-containing or efavirenz-free ARV regimen with ≥6 months of continuous insurance enrollment prior to ARV initiation were selected. The primary outcome was suicidality, defined as the occurrence of any medical claim with a diagnosis code for suicidal ideation or an inpatient or emergency department medical claim for suicide attempt. Unadjusted incidence rates were calculated and propensity score-adjusted hazard ratios were estimated to account for differences in patient characteristics.There were 19,983 patients (efavirenz-containing, n = 11,187; efavirenz-free, n = 8796) in the commercial database and 5154 patients (efavirenz-containing, n = 2224; efavirenz-free, n = 2930) in the Medicaid database. Unadjusted incidence rates (95% confidence interval [CI]) of suicidality per 1000 person-years were: commercial, efavirenz-containing (3.3 [2.4-4.4]), efavirenz-free (4.0 [2.7-5.8]); Medicaid, efavirenz-containing (25.7 [18.8-34.4]), efavirenz-free (40.6 [31.9-50.9]). In propensity score-adjusted analyses, efavirenz use was not associated with suicidality: adjusted hazard ratio (95% CI) of suicidality compared with efavirenz-free regimen, commercial, 1.029 (0.636-1.665); Medicaid, 0.902 (0.617-1.319).This analysis found no conclusive evidence of an increased risk of suicidality among patients initiating an efavirenz-containing ARV regimen. However, channeling bias may exist even after adjusting for measured patient characteristics.

Topiramate use during pregnancy and major congenital malformations in multiple populations.

BACKGROUND: We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. METHODS: Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. RESULTS: Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. CONCLUSION: To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

Topiramate use in pregnancy and the birth prevalence of oral clefts.

PURPOSE: First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC. METHODS: This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles. RESULTS: The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results. CONCLUSION: Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

The effect of HIV infection on the risk, frequency, and intensity of Plasmodium falciparum parasitemia in primigravid and multigravid women in Malawi.

Human immunodeficiency virus (HIV) is common in pregnant women in many malaria-endemic regions and may increase risk of placental parasitemia. Placental malaria is more common in primigravidae than multigravidae, but the relationship between HIV and malaria across gravidities is not well characterized. We recruited pregnant Malawian women during the second trimester and followed them until delivery. Parasitemia was assessed at enrollment, follow-up visits, and delivery, when placental blood was sampled. There was no difference in risk of parasitemia between HIV-positive and HIV-negative primigravidae. Among multigravidae, HIV-infected women had greater than twice the risk of parasitemia as HIV-uninfected women throughout follow-up. Human immunodeficiency virus was also associated with more frequent peripheral parasitemia in multigravidae but not primigravidae. Both HIV and primigravid status were independently associated with higher peripheral and placental parasite densities. Although risk of parasitemia is lower in multigravidae than primigravidae, the HIV effect on risk of malaria is more pronounced in multigravidae.

Effect of HIV infection and Plasmodium falciparum parasitemia on pregnancy outcomes in Malawi.

Plasmodium falciparum and human immunodeficiency virus (HIV) are both risk factors for low birth weight (LBW) and maternal anemia, and they may interact to increase risk of adverse pregnancy outcomes. In 2005 and 2006, we followed 831 pregnant women attending antenatal care clinics in southern Malawi through delivery. HIV was associated with increased risk of LBW (adjusted prevalence ratio [PR(adj)] = 3.08, 95% confidence interval [CI] = 1.40, 6.79). Having greater than or equal to three episodes of peripheral parasitemia was also associated with increased risk of LBW (PR(adj) = 2.68, 95% CI = 1.06, 6.79). Among multigravidae, dual infection resulted in 9.59 (95% CI = 2.51, 36.6) times the risk of LBW compared with uninfected multigravidae. HIV infection and placental parasitemia were each associated with increased risk of anemia. Thus, HIV infection and parasitemia are important independent risk factors for adverse pregnancy outcomes. Among multigravidae, HIV infection and placental parasitemia may interact to produce an impact greater than the sum of their independent effects.

Prevalence, severity, and duration of thrombocytopenia among HIV patients in the era of highly active antiretroviral therapy.

Thrombocytopenia is a clinically relevant outcome in HIV. However, the epidemiology of this condition, including frequency, severity, and duration, has not been well-characterized in the era of highly active antiretroviral therapy (HAART). In this study, we describe the epidemiology of thrombocytopenia using two methods. We conducted a systematic review of the literature published between 1997 and 2009 to characterize the frequency of thrombocytopenia in different populations in the HAART era. Secondly, we examined the frequency, severity, and duration of thrombocytopenia among HIV patients in the Collaborations in HIV Outcomes Research/US (CHORUS) Cohort from 1997 to 2006 and among HIV patients participating in GlaxoSmithKline HIV Clinical Trials between 1996 and 2004. Prevalence estimates of thrombocytopenia (<150 000 platelets/µl) in the literature varied greatly but were generally above 10%. The thrombocytopenia prevalence estimates in the CHORUS Cohort and the HIV Clinical Trials were both 14%. In the CHORUS Cohort, the platelet count was ≤50 000/µl among 3.1% and ≤30 000/µl among 1.7%; in the HIV clinical trials database, the platelet count was ≤50 000/µl among 1.3% and ≤30 000/µl among 0.67%. Duration of severe thrombocytopenia varied greatly, with the medium duration to ≥75 000 platelets/µl taking 147 days in the CHORUS Cohort and 33 days in the HIV clinical trials database. Among 111 patients with severe thrombocytopenia in the CHORUS Cohort, 23% never achieved a higher platelet count over follow-up. In conclusion, while the prevalence of severe thrombocytopenia was low, it occurred at levels associated with bleeding and was persistent among a small proportion of patients despite receipt of HAART.

The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis.

Glucose-6-phosphate deficiency is the most prevalent enzyme deficiency, with an estimated 400 million people affected worldwide. This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia. Although most affected individuals are asymptomatic, exposure to oxidative stressors such as certain drugs or infection, can elicit acute hemolysis. To characterize the global prevalence of G6PD deficiency, we conducted a systematic review of the G6PD deficiency literature, drawing studies from various databases, including MEDLINE/Pubmed and Biosis. Selected studies included cross-sectional and longitudinal studies published between 1960 and 2008. Additionally, meta-analytic procedures were employed to assess the degree of heterogeneity amongst prevalence estimates and, where appropriate, pool them. The searches yielded a total of 280 prevalence estimates, corresponding to 88 countries. The highest prevalence rates were reported among Sub-Saharan African countries, even after adjusting for assessment method. Meta-analysis revealed a high degree of heterogeneity for regional and global prevalence estimates. This heterogeneity in reported estimates appeared to be due to differences in G6PD deficiency assessment and diagnostic procedures. The magnitude and variation in global, regional, and country-level prevalence rates of G6PD deficiency are of public health import, particularly in planning programs to improve neonatal health and in the distribution of various medications, especially antimalarial drugs, as G6PD deficiency is most prevalent in malaria-endemic areas.

Examining geographic and temporal variations of AIDS mortality: evidence of racial disparities.

BACKGROUND: There is little literature on spatiotemporal trends of AIDS mortality among different race and gender groups. The purpose of the present study is to describe AIDS mortality geographically and temporally, and to determine if detected trends vary by race and gender. METHODS: The Spatial Scan Statistic was employed to examine the geographic excess of AIDS mortality by race and gender in 24 Maryland jurisdictions between 1987 and 2003. Spatial analysis was conducted to identify clusters of excess mortality. The temporal scan statistic was used to explore time trends of AIDS mortality. Prospective space-time analysis was also conducted to verify if detected clusters persisted into the present. RESULTS: Among 10,887 AIDS deaths, 77.5% occurred in African Americans. Geographic excesses of AIDS mortality were detected in Baltimore city, and Howard, Montgomery, Anne Arundel, Prince Georges and Baltimore counties. Over the study period, AIDS mortality peaked in 1995 and then sharply dropped until 1998, when it stabilized. However, the AIDS mortality of African-American women started oscillating upward in 1998. CONCLUSION: This study quantitatively described geographic and temporal variations of AIDS mortality in Maryland by gender and racial groups. The results may inform development of programs to address HIV/AIDS while considering the groups most affected differentially by geographic area.

A new application of spatiotemporal analysis for detecting demographic variations in AIDS mortality: an example from Florida.

The purpose of the present study was to characterize, geographically and temporally, the patterns of acquired immune deficiency syndrome (AIDS) death disparity in 67 Florida jurisdictions, and to determine if the detected trends varied according to age, race, and sex. The space-time scan statistic proposed by Kulldorff et al was used to examine the excess AIDS deaths that occurred between 1987 and 2004. Results were geographically referenced in maps using EpiInfo and EpiMap made available by the Centers for Disease Control. Miami-Dade and the nearby counties including Broward, Martin, and Palm Beach are the most likely clusters (observed/expected: 1505.16) with temporal dimension (also called cluster's age) persisting from 1996 to the present. Union county had the longest cluster for the cluster period 1987-1998, but not for 1999-2004. African-Americans contributed to more clusters compared with whites. Time trends indicated that AIDS mortality peaked in 1995 and then sharply dropped until 1998, when the decrease stopped. By accounting for the temporal dimension of disease clustering, the present study revealed the persistence of geographic clusters, which is not often provided by other geographic detection methods. These findings may be informative for medical resource allocation and better focus public health intervention strategies for AIDS care.

A spatial-temporal approach to surveillance of prostate cancer disparities in population subgroups.

BACKGROUND: Prostate cancer mortality disparities exist among racial/ethnic groups in the United States, yet few studies have explored the spatiotemporal trend of the disease burden. To better understand mortality disparities by geographic regions over time, the present study analyzed the geographic variations of prostate cancer mortality by three Texas racial/ethnic groups over a 22-year period. METHODS: The Spatial Scan Statistic developed by Kulldorff et al was used. Excess mortality was detected using scan windows of 50% and 90% of the study period and a spatial cluster size of 50% of the population at risk. Time trend was analyzed to examine the potential temporal effects of clustering. Spatial queries were used to identify regions with multiple racial/ethnic groups having excess mortality. RESULTS: The most likely area of excess mortality for blacks occurred in Dallas-Metroplex and upper east Texas areas between 1990 and 1999; for Hispanics, in central Texas between 1992 and 1996: and for non-Hispanic whites, in the upper south and west to central Texas areas between 1990 and 1996. Excess mortality persisted among all racial/ethnic groups in the identified counties. The second scan revealed that three counties in west Texas presented an excess mortality for Hispanics from 1980-2001. Many counties bore an excess mortality burden for multiple groups. There is no time trend decline in prostate cancer mortality for blacks and non-Hispanic whites in Texas. CONCLUSION: Disparities in prostate cancer mortality among racial/ethnic groups existed in Texas. Central Texas counties with excess mortality in multiple subgroups warrant further investigation.

Public health preparedness of health providers: meeting the needs of diverse, rural communities.

Meeting the needs of public health emergency and response presents a unique challenge for health practitioners with primary responsibilities for rural communities that are often very diverse. The present study assessed the language capabilities, confidence and training needs of Texas rural physicians in responding to public health emergencies. In the first half of year 2004, a cross-sectional, semistructured survey questionnaire was administered in northern, rural Texas. The study population consisted of 841 practicing or retired physicians in the targeted area. One-hundred-sixty-six physicians (30%) responded to the survey. The responses were geographically referenced in maps. Respondents reported seeing patients with diverse cultural backgrounds. They communicated in 16 different languages other than English in clinical practice or at home, with 40% speaking Spanish at work. Most were not confident in the diagnosis or treatment of public health emergency cases. Geographic information systems were found useful in identifying those jurisdictions with expressed training and cultural needs. Additional efforts should be extended to involve African-American/Hispanic physicians in preparedness plans for providing culturally and linguistically appropriate care in emergencies.

Assessing the readiness and training needs of non-urban physicians in public health emergency and response.

Emergency readiness has become a public health priority for United States communities after the 9/11 attacks. Communities that have a less developed public health infrastructure are challenged to organize preparedness and response efforts and to ensure that health care providers are capable of caring for victims of terrorist acts. A survey was used to assess non-urban physicians' prior experience with and self-confidence in treating, and preferred training needs for responding to chemical, biologic, radiologic, nuclear, and explosive (CBRNE) cases. Data were collected through a mailed and Web-based survey. Although the response rate was calculated at 30%, approximately one third of the surveys were not able to be delivered. Most respondents reported never having seen or treated CBRNE-inflicted cases and were not confident in their ability to diagnose or treat CBRNE cases, but many were willing to participate in a state-led response plan. Almost half of the individuals had not participated in any related training but expressed interest in receiving training in small group workshops or through CD-ROM. These results provide potential direction for strategic preparedness planning for non-urban health care providers.

Detecting spatiotemporal clusters of accidental poisoning mortality among Texas counties, U.S., 1980 - 2001.

BACKGROUND: Accidental poisoning is one of the leading causes of injury in the United States, second only to motor vehicle accidents. According to the Centers for Disease Control and Prevention, the rates of accidental poisoning mortality have been increasing in the past fourteen years nationally. In Texas, mortality rates from accidental poisoning have mirrored national trends, increasing linearly from 1981 to 2001. The purpose of this study was to determine if there are spatiotemporal clusters of accidental poisoning mortality among Texas counties, and if so, whether there are variations in clustering and risk according to gender and race/ethnicity. The Spatial Scan Statistic in combination with GIS software was used to identify potential clusters between 1980 and 2001 among Texas counties, and Poisson regression was used to evaluate risk differences. RESULTS: Several significant (p < 0.05) accidental poisoning mortality clusters were identified in different regions of Texas. The geographic and temporal persistence of clusters was found to vary by racial group, gender, and race/gender combinations, and most of the clusters persisted into the present decade. Poisson regression revealed significant differences in risk according to race and gender. The Black population was found to be at greatest risk of accidental poisoning mortality relative to other race/ethnic groups (Relative Risk (RR) = 1.25, 95% Confidence Interval (CI) = 1.24 - 1.27), and the male population was found to be at elevated risk (RR = 2.47, 95% CI = 2.45 - 2.50) when the female population was used as a reference. CONCLUSION: The findings of the present study provide evidence for the existence of accidental poisoning mortality clusters in Texas, demonstrate the persistence of these clusters into the present decade, and show the spatiotemporal variations in risk and clustering of accidental poisoning deaths by gender and race/ethnicity. By quantifying disparities in accidental poisoning mortality by place, time and person, this study demonstrates the utility of the spatial scan statistic combined with GIS and regression methods in identifying priority areas for public health planning and resource allocation.