Generalizing Evidence from Randomized Trials using Inverse Probability of Sampling Weights

Results obtained in randomized trials may not easily generalize to target populations. Whereas in randomized trials the treatment assignment mechanism is known, the sampling mechanism by which individuals are selected to participate in the trial is typically not known and assuming random sampling from the target population is often dubious. We consider an inverse probability of sampling weighted (IPSW) estimator for generalizing trial results to a target population. The IPSW estimator is shown to be consistent and asymptotically normal. A consistent sandwich-type variance estimator is derived and simulation results are presented comparing the IPSW estimator to a previously proposed stratified estimator. The methods are then utilized to generalize results from two randomized trials of HIV treatment to all people living with HIV in the US

Effects of Plasma HIV RNA, CD4+ T Lymphocytes, and the Chemokine Receptors CCR5 and CCR2b on HIV Disease Progression in Hemophiliacs

We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genotype variants CCR2b-641 and CCR5-Δ32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number

Deferasirox (Exjade®) significantly improves cardiac T2* in heavily iron-overloaded patients with β-thalassemia major

Noninvasive measurement of tissue iron levels can be assessed using T2* magnetic resonance imaging (MRI) to identify and monitor patients with iron overload. This study monitored cardiac siderosis using T2* MRI in a cohort of 19 heavily iron-overloaded patients with β-thalassemia major receiving iron chelation therapy with deferasirox over an 18-month period. Overall, deferasirox therapy significantly improved mean ± standard deviation cardiac T2* from a baseline of 17.2 ± 10.8 to 21.5 ± 12.8 ms (+25.0%; P = 0.02). A concomitant reduction in median serum ferritin from a baseline of 5,497 to 4,235 ng/mL (−23.0%; P = 0.001), and mean liver iron concentration from 24.2 ± 9.0 to 17.6 ± 12.9 mg Fe/g dry weight (−27.1%; P = 0.01) was also seen. Improvements were seen in patients with various degrees of cardiac siderosis, including those patients with a baseline cardiac T2* of <10 ms, indicative of high cardiac iron burden. These findings therefore support previous observations that deferasirox is effective in the removal of myocardial iron with concomitant reduction in total body iron

Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion

Predictors of CNS Injury as Measured by Proton Magnetic Resonance Spectroscopy in the Setting of Chronic HIV infection and CART

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS) Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr and Glx/Cr) were measured in the basal ganglia, the frontal white matter and grey matter and the best predictive models were selected using a bootstrap-enhanced Akaike Information Criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease

A global framework for action to improve the primary care response to chronic non-communicable diseases: a solution to a neglected problem.

BACKGROUND: Although in developing countries the burden of morbidity and mortality due to infectious diseases has often overshadowed that due to chronic non-communicable diseases (NCDs), there is evidence now of a shift of attention to NCDs. DISCUSSION: Decreasing the chronic NCD burden requires a two-pronged approach: implementation of the multisectoral policies aimed at decreasing population-level risks for NCDs, and effective and affordable delivery of primary care interventions for patients with chronic NCDs. The primary care response to common NCDs is often unstructured and inadequate. We therefore propose a programmatic, standardized approach to the delivery of primary care interventions for patients with NCDs, with a focus on hypertension, diabetes mellitus, chronic airflow obstruction, and obesity. The benefits of this approach will extend to patients with related conditions, e.g. those with chronic kidney disease caused by hypertension or diabetes. This framework for a "public health approach" is informed by experience of scaling up interventions for chronic infectious diseases (tuberculosis and HIV). The lessons learned from progress in rolling out these interventions include the importance of gaining political commitment, developing a robust strategy, delivering standardised interventions, and ensuring rigorous monitoring and evaluation of progress towards defined targets. The goal of the framework is to reduce the burden of morbidity, disability and premature mortality related to NCDs through a primary care strategy which has three elements: 1) identify and address modifiable risk factors, 2) screen for common NCDs and 3) and diagnose, treat and follow-up patients with common NCDs using standard protocols. The proposed framework for NCDs borrows the same elements as those developed for tuberculosis control, comprising a goal, strategy and targets for NCD control, a package of interventions for quality care, key operations for national implementation of these interventions (political commitment, case-finding among people attending primary care services, standardised diagnostic and treatment protocols, regular drug supply, and systematic monitoring and evaluation), and indicators to measure progress towards increasing the impact of primary care interventions on chronic NCDs. The framework needs evaluation, then adaptation in different settings. SUMMARY: A framework for a programmatic "public health approach" has the potential to improve on the current unstructured approach to primary care of people with chronic NCDs. Research to establish the cost, value and feasibility of implementing the framework will pave the way for international support to extend the benefit of this approach to the millions of people worldwide with chronic NCDs

Effect of Treatment, during Primary Infection, on Establishment and Clearance of Cellular Reservoirs of HIV-1

Patients in whom virologic suppression is achieved with highly active antiretroviral therapy (HAART) retain long-lived cellular reservoirs of human immunodeficiency virus type 1 (HIV-1); this retention is an obstacle to sustained control of infection. To assess the impact that initiating treatment during primary HIV-1 infection has on this cell population, we analyzed the decay kinetics of HIV-1 DNA and of infectivity associated with cells activated ex vivo in 27 patients who initiated therapy before or <6 months after seroconversion and in whom viremia was suppressed to <50 copies/mL. The clearance rates of cellular reservoirs could not be distinguished by these techniques (median half-life, 20 weeks) during the first year of HAART. The clearance of HIV-1 DNA slowed significantly during the subsequent 3 years of treatment (median half-life, 70 weeks), consistent with heterogeneous cellular reservoirs being present. Total cell-associated infectivity (CAI) after 1 year of treatment was undetectable (<0.07 infectious units/million cells [IUPM]) in most patients initiating treatment during primary infection either before (9/9) or <6 months after (6/8) seroconversion. In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment (median reservoir size, 1.1 IUPM; P<.0005). These results suggest that treatment <6 months after seroconversion may facilitate long-term control of cellular reservoirs that maintain HIV-1 infection during treatmen

Validity and Characterization of Time to Symptom Resolution Outcome Measures in the ACTIV-2/A5401 Outpatient COVID-19 Treatment Trial

BackgroundTime to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation.MethodsACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo.ResultsThe analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring &gt;2 days to define sustained resolution reduced the frequency of recurrences.ConclusionsThere was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring &gt;2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms.Clinical trials registrationNCT04518410