Virologic suppression and CD4 + cell count recovery after initiation of raltegravir or efavirenz-containing HIV treatment regimens

Objective: To explore the effectiveness of raltegravir-based antiretroviral therapy (ART) on treatment response among ART-naive patients seeking routine clinical care. Design: Cohort study of adults enrolled in HIV care in the United States. Methods: We compared virologic suppression and CD4 + cell count recovery over a 2.5 year period after initiation of an ART regimen containing raltegravir or efavirenz using observational data from a US clinical cohort, generalized to the US population of people with diagnosed HIV. We accounted for nonrandom treatment assignment, informative censoring, and nonrandom selection from the US target population using inverse probability weights. Results: Of the 2843 patients included in the study, 2476 initiated the efavirenz-containing regimen and 367 initiated the raltegravir-containing regimen. In the weighted intent-To-Treat analysis, patients spent an average of 74 (95% confidence interval: 41, 106) additional days alive with a suppressed viral load on the raltegravir regimen than on the efavirenz regimen over the 2.5-year study period. CD4 + cell count recovery was also superior under the raltegravir regimen. Conclusion: Patients receiving raltegravir spent more time alive and suppressed than patients receiving efavirenz, but the probability of viral suppression by 2.5 years after treatment was similar between groups. Optimizing the amount of time spent in a state of viral suppression is important to improve survival among people living with HIV and to reduce onward transmission

Generalizing the per-protocol treatment effect: The case of ACTG A5095

Background Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population. Methods We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008–2014. Results Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2 years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was −0.4 (95% confidence interval: −6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was −0.9 (95% confidence interval: −6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio = 0.95, 95% confidence interval: 0.68, 1.32) and −0.7 (95% confidence interval: −6.7, 5.5) for the per-protocol comparison (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). Conclusion No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population

Demographic Trends in US HIV Diagnoses, 2008–2017: Data Movies

In this editorial, we introduce the data movie as a tool for investigating and communicating changing patterns of disease using the example of HIV in the United States. The Centers for Disease Control and Prevention currently tracks all new HIV diagnoses through the National HIV Surveillance System. Understanding what these data tell us is critical to the goal of ending the HIV epidemic in the United States.1 However, summarizing trends across multiple population characteristics simultaneously—for example, exploring how the age distribution of new diagnoses varies by geographic region and how that relationship has changed over time—can be difficult. Because data movies allow us to visualize complex relationships more easily than large tables or paneled figures, they can help us take full advantage of our increasingly rich national surveillance data

Relationship of Racial Residential Segregation to Newly Diagnosed Cases of HIV among Black Heterosexuals in US Metropolitan Areas, 2008–2015

Social science and public health literature has framed residential segregation as a potent structural determinant of the higher HIV burden among black heterosexuals, but empirical evidence has been limited. The purpose of this study is to test, for the first time, the association between racial segregation and newly diagnosed heterosexually acquired HIV cases among black adults and adolescents in 95 large US metropolitan statistical areas (MSAs) in 2008–2015. We operationalized racial segregation (the main exposure) using Massey and Denton’s isolation index for black residents; the outcome was the rate of newly diagnosed HIV cases per 10,000 black adult heterosexuals. We tested the relationship of segregation to this outcome using multilevel multivariate models of longitudinal (2008–2015) MSA-level data, controlling for potential confounders and time. All covariates were lagged by 1 year and centered on baseline values. We preliminarily explored mediation of the focal relationship by inequalities in education, employment, and poverty rates. Segregation was positively associated with the outcome: a one standard deviation decrease in baseline isolation was associated with a 16.2% reduction in the rate of new HIV diagnoses; one standard deviation reduction in isolation over time was associated with 4.6% decrease in the outcome. Exploratory mediation analyses suggest that black/white socioeconomic inequality may mediate the relationship between segregation and HIV. Our study suggests that residential segregation may be a distal determinant of HIV among black heterosexuals. The findings further emphasize the need to address segregation as part of a comprehensive strategy to reduce racial inequities in HIV

Evidence for HIV transmission across key populations: a longitudinal analysis of HIV and AIDS rates among Black people who inject drugs and Black heterosexuals in 84 large U.S. metropolitan areas, 2008–2016

Purpose: To assess cross-population linkages in HIV/AIDS epidemics, we tested the hypothesis that the number of newly diagnosed AIDS cases among Black people who inject drugs (PWID) was positively related to the natural log of the rate of newly diagnosed HIV infections among Black non-PWID heterosexuals in 84 large U.S. metropolitan statistical areas (MSAs) in 2008–2016. Methods: We estimated a multilevel model centering the time-varying continuous exposures at baseline between the independent (Black PWID AIDS rates) and dependent (HIV diagnoses rate among Black heterosexuals) variables. Results: At MSA level, baseline (standardized β = 0.12) Black PWID AIDS rates and change in these rates over time (standardized β = 0.11) were positively associated with the log of new HIV diagnoses rates among Black heterosexuals. Thus, MSAs with Black PWID AIDS rates that were 1 standard deviation= higher at baseline also had rates of newly diagnosed HIV infections among Black non-PWID heterosexuals that were 10.3% higher. A 1 standard deviation increase in independent variable over time corresponded to a 7.8% increase in dependent variable. Conclusions: Black PWID AIDS rates may predict HIV rates among non-PWID Black heterosexuals. Effective HIV programming may be predicated, in part, on addressing intertwining of HIV epidemics across populations

State minimum wage laws and newly diagnosed cases of HIV among heterosexual black residents of US metropolitan areas

This ecologic cohort study explores the relationship between state minimum wage laws and rates of HIV diagnoses among heterosexual black residents of U.S metropolitan areas over an 8-year span. Specifically, we applied hierarchical linear modeling to investigate whether state-level variations in minimum wage laws, adjusted for cost-of-living and inflation, were associated with rates of new HIV diagnoses among heterosexual black residents of metropolitan statistical areas (MSAs; n=73), between 2008 and 2015. Findings suggest that an inverse relationship exists between baseline state minimum wages and initial rates of newly diagnosed HIV cases among heterosexual black individuals, after adjusting for potential confounders. MSAs with a minimum wage that was $1 higher at baseline had a 27.12% lower rate of newly diagnosed HIV cases. Exploratory analyses suggest that income inequality may mediate this relationship. If subsequent research establishes a causal relationship between minimum wage and this outcome, efforts to increase minimum wages should be incorporated into HIV prevention strategies for this vulnerable population

Assessment and improvement of the Plasmodium yoelii yoelii genome annotation through comparative analysis

Motivation: The sequencing of the Plasmodium yoelii genome, a model rodent malaria parasite, has greatly facilitated research for the development of new drug and vaccine candidates against malaria. Unfortunately, only preliminary gene models were annotated on the partially sequenced genome, mostly by in silico gene prediction, and there has been no major improvement of the annotation since 2002

Calsequestrin as a risk factor in Graves’ hyperthyroidism and Graves’ ophthalmopathy patients

Background: The pathogenesis of Graves’ ophthalmopathy (GO), Graves’ hyperthyroidism (GH) and the mechanisms for its link to thyroid autoimmunity are poorly understood. Our research focuses on the role of the skeletal muscle calcium binding protein calsequestrin (CASQ1) in thyroid. We measured the concentration of the CASQ1 protein correlating levels with parameters of the eye signs, CASQ1 antibody levels and CASQ1 gene polymorphism rs3838284. Methods: CASQ1 protein was measured by quantitative Western Blotting. The protein concentrations were expressed as pmol/mg total protein by reference to CASQ1 standards. Results: Western blot analysis showed the presence of two forms of CASQ1 in the thyroid. The mean concentration of CASQ1 protein was significantly reduced in patients with Graves’ disease, compared to thyroid from control subjects with multi-nodular goitre or thyroid cancer. Although in patients with GO it was lower than that, compared with patients with GH this difference was not significant. Reduced CASQ1 in Graves’ thyroid correlated with the homozygous genotype of the rs3838284 CASQ1 polymorphism. Conclusions: Decreased CASQ1 in the thyroid of patients with Graves’ disease compared to thyroid from control subjects is not explained but may reflect consumption of the protein during an autoimmune reaction against CASQ1 in the thyroid

Incident AIDS or death after initiation of human immunodeficiency virus treatment regimens including raltegravir or efavirenz among adults in the United States

Background. The long-term effectiveness of human immunodeficiency virus (HIV) treatments containing integrase inhibitors is unknown. Methods. We use observational data from the Centers for AIDS Research Network of Integrated Clinical Systems and the Centers for Disease Control and Prevention to estimate 4-year risk of AIDS and all-cause mortality among 415 patients starting a raltegravir regimen compared to 2646 starting an efavirenz regimen (both regimens include emtricitabine and tenofovir disoproxil fumarate). We account for confounding and selection bias as well as generalizability by standardization for measured variables, and present both observational intent-to-treat and per-protocol estimates. Results. At treatment initiation, 12% of patients were female, 36% black, 13% Hispanic; median age was 37 years, CD4 count 321 cells/µL, and viral load 4.5 log10 copies/mL. Two hundred thirty-five patients incurred an AIDS-defining illness or died, and 741 patients left follow-up. After accounting for measured differences, the 4-year risk was similar among those starting both regimens (ie, intent-to treat hazard ratio [HR], 0.96 [95% confidence interval {CI}, .63–1.45]; risk difference, −0.9 [95% CI, −4.5 to 2.7]), as well as among those remaining on regimens (ie, per-protocol HR, 0.95 [95% CI, .59–1.54]; risk difference, −0.5 [95% CI, −3.8 to 2.9]). Conclusions. Raltegravir and efavirenz-based initial antiretroviral therapy have similar 4-year clinical effects. Vigilance regarding longer-term comparative effectiveness of HIV regimens using observational data is needed because large-scale experimental data are not forthcoming