Tuan D. Le

Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy

BACKGROUND The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with human immunodeficiency virus type 1 (HIV-1) and the recovery of CD4+ T-cell counts is unknown. METHODS In a prospective, observational cohort of persons with acute or early HIV-1 infection, we determined the trajectory of CD4+ counts over a 48-month period in partially overlapping study sets: study set 1 included 384 participants during the time window in which they were not receiving ART and study set 2 included 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load. We investigated the likelihood and rate of CD4+ T-cell recovery to 900 or more cells per cubic millimeter within 48 months while the participants were receiving viral-load-suppressive ART. RESULTS Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P<0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery. CONCLUSIONS A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Duffy-Null–Associated Low Neutrophil Counts Influence HIV-1 Susceptibility in High-Risk South African Black Women

BACKGROUND The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)-1 infection among Africans is unknown. METHODS The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. RESULTS Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm(3) had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10(-11)). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm(3). The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null-associated low neutrophil counts, compared with all other study participants. CONCLUSIONS Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null-associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.

Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals

IMPORTANCE In individuals with human immunodeficiency virus 1 (HIV-1) infection who are receiving antiretroviral therapy (ART), factors that promote full immune recovery are not well characterized. OBJECTIVE To investigate the influence of the timing of ART relative to HIV-1 infection on normalization of CD4+ T-cell counts, AIDS risk, and immune function. DESIGN, SETTING, AND PARTICIPANTS Participants in the observational US Military HIV Natural History Study with documented estimated dates of seroconversion (EDS) who achieved virologic suppression with ART were evaluated. Markers indicative of immune activation, dysfunction, and responsiveness were determined. Responses to hepatitis B virus (HBV) vaccine, an indicator of in vivo immune function, were also assessed. The timing of ART was indexed to the EDS and/or entry into the cohort. The CD4+ counts in HIV-1-uninfected populations were surveyed. MAIN OUTCOMES AND MEASURES Normalization of CD4+ counts to 900 cells/μL or higher, AIDS development, HBV vaccine response, as well as T-cell activation, dysfunction, and responsiveness. RESULTS The median CD4+ count in HIV-1-uninfected populations was approximately 900 cells/μL. Among 1119 HIV-1-infected participants, CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months vs after 12 months from the EDS (P = .001). Incrementally higher CD4+ recovery (<500, 500-899, and ≥900 cells/μL) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation, dysfunction, and responsiveness to levels approximating those found in HIV-1-uninfected persons. Participants with CD4+ counts of 500 cells/μL or higher at study entry (adjusted odds ratio [aOR], 2.00; 95% CI, 1.51-2.64; P < .001) or ART initiation (aOR, 4.08; 95% CI, 3.14-5.30; P < .001) had significantly increased CD4+ normalization rates compared with other participants. However, even among individuals with a CD4+ count of 500 cells/μL or higher at both study entry and before ART, the odds of CD4+ normalization were 80% lower in those initiating ART after 12 months from the EDS and study entry (aOR, 0.20; 95% CI, 0.07-0.53; P = 001). Initiation of ART within 12 months of EDS vs later was associated with a significantly lower risk of AIDS (7.8% vs 15.3%; P = .002), reduced T-cell activation (percent CD4+HLA-DR+ effector memory T cells, 12.0% vs 15.6%; P = .03), and increased responsiveness to HBV vaccine (67.9% vs 50.9%; P = .07). CONCLUSIONS AND RELEVANCE Deferral of ART beyond 12 months of the EDS diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals.

The rs1024611 Regulatory Region Polymorphism Is Associated with CCL2 Allelic Expression Imbalance

CC chemokine ligand 2 (CCL2) is the most potent monocyte chemoattractant and inter-individual differences in its expression level have been associated with genetic variants mapping to the cis-regulatory regions of the gene. An A to G polymorphism in the CCL2 enhancer region at position –2578 (rs1024611; A>G), was found in most studies to be associated with higher serum CCL2 levels and increased susceptibility to a variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis. However, the precise mechanism by which rs1024611influences CCL2 expression is not known. To address this knowledge gap, we tested the hypothesis that rs1024611G polymorphism is associated with allelic expression imbalance (AEI) of CCL2. We used haplotype analysis and identified a transcribed SNP in the 3′UTR (rs13900; C>T) can serve as a proxy for the rs1024611 and demonstrated that the rs1024611G allele displayed a perfect linkage disequilibrium with rs13900T allele. Allele-specific transcript quantification in lipopolysaccharide treated PBMCs obtained from heterozygous donors showed that rs13900T allele were expressed at higher levels when compared to rs13900C allele in all the donors examined suggesting that CCL2 is subjected to AEI and that that the allele containing rs1024611G is preferentially transcribed. We also found that AEI of CCL2 is a stable trait and could be detected in newly synthesized RNA. In contrast to these in vivo findings, in vitro assays with haplotype-specific reporter constructs indicated that the haplotype bearing rs1024611G had a lower or similar transcriptional activity when compared to the haplotype containing rs1024611A. This discordance between the in vivo and in vitro expression studies suggests that the CCL2 regulatory region polymorphisms may be functioning in a complex and context-dependent manner. In summary, our studies provide strong functional evidence and a rational explanation for the phenotypic effects of the CCL2 rs1024611G allele.

Effects of cardiorespiratory fitness on serum ferritin concentration and incidence of type 2 diabetes: Evidence from the Aerobics Center Longitudinal Study (ACLS)

BACKGROUND Cardiorespiratory fitness (CRF) and physical activity (PA) are inversely related to the occurrence of type 2 diabetes (T2D). Both play an important role in reducing serum ferritin (SF) concentration. Increased SF concentration is considered a contributing factor for developing T2D. METHODS The present cohort study investigated 5,512 adult participants enrolled in the Aerobics Center Longitudinal Study (ACLS) between 1995 and 2001. The subjects completed a comprehensive medical examination and a SF evaluation, and had been followed up until either diabetes onset, death, or the cut-off date of November 2007. Three CRF levels were categorized. SF quartile levels were defined by gender and menopausal status. The incidence of T2D was calculated for 10,000 person-years, and hazard ratios (HR) were computed to predict the incidence of T2D based on SF quartiles and CRF levels. RESULTS SF concentration was significantly higher in males than in females (148.5 +/- 104.7 ng/ml vs. 52.2 +/- 45.9 ng/ml) and was inversely associated with CRF levels. In the high CRF group, 32.7% of participants had a low SF concentration whereas only 16.8% of participants had a high SF concentration level. After adjusting for potential confounders, male participants in the highest SF quartile level had a 1.7 times (HR: 1.67, 95% CI: 1.05, 2.66; p-trend = 0.027) increased risk for developing T2D compared with those in the lowest SF quartile group. CONCLUSION Lower SF concentration was associated with lower risk of developing T2D in those regularly participating in CRF. The findings from this study suggest that SF concentration could be used as a diabetic predictor. Based on these results clinicians and public health professionals should promote regular physical activity or fitness to reduce the incidence of T2D.

The military injury severity score (mISS): A better predictor of combat-mortality than injury severity score (ISS)

BACKGROUND The Military Injury Severity Score (mISS) was developed to better predict mortality in complex combat injuries but has yet to be validated. METHODS US combat trauma data from Afghanistan and Iraq from January 1, 2003, to December 31, 2014, from the US Department of Defense Trauma Registry (DoDTR) were analyzed. Military ISS, a variation of the ISS, was calculated and compared with standard ISS scores. Receiver operating characteristic curve, area under the curve, and Hosmer-Lemeshow statistics were used to discriminate and calibrate between mISS and ISS. Wilcoxon-Mann-Whitney, t test and &khgr;2 tests were used, and sensitivity and specificity calculated. Logistic regression was used to calculate the likelihood of mortality associated with levels of mISS and ISS overall. RESULTS Thirty thousand three hundred sixty-four patients were analyzed. Most were male (96.8%). Median age was 24 years (interquartile range [IQR], 21–29 years). Battle injuries comprised 65.3%. Penetrating (39.5%) and blunt (54.2%) injury types and explosion (51%) and gunshot wound (15%) mechanisms predominated. Overall mortality was 6.0%. Median mISS and ISS were similar in survivors (5 [IQR, 2–10] vs. 5 [IQR, 2–10]) but different in nonsurvivors, 30 (IQR, 16–75) versus 24 (IQR, 9–23), respectively (p < 0.0001). Military ISS and ISS were discordant in 17.6% (n = 5,352), accounting for 56.2% (n = 1,016) of deaths. Among cases with discordant severity scores, the median difference between mISS and ISS was 9 (IQR, 7–16); range, 1 to 59. Military ISS and ISS shared 78% variability (R2 = 0.78). Area under the curve was higher in mISS than in ISS overall (0.82 vs. 0.79), for battle injury (0.79 vs. 0.76), non–battle injury (0.87 vs. 0.86), penetrating (0.81 vs. 0.77), blunt (0.77 vs. 0.75), explosion (0.81 vs. 0.78), and gunshot (0.79 vs. 0.73), all p < 0.0001. Higher mISS and ISS were associated with higher mortality. Compared with ISS, mISS had higher sensitivity (81.2 vs. 63.9) and slightly lower specificity (80.2 vs. 85.7). CONCLUSION Military ISS predicts combat mortality better than does ISS. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

Evaluation of role 2 (R2) medical resources in the Afghanistan combat theater: Initial review of the joint trauma system R2 registry.

BACKGROUND A Role 2 registry (R2R) was developed in 2008 by the US Joint Trauma System (JTS). The purpose of this project was to undertake a preliminary review of the R2R to understand combat trauma epidemiology and related interventions at these facilities to guide training and optimal use of forward surgical capability in the future. METHODS A retrospective review of available JTS R2R records; the registry is a convenience sample entered voluntarily by members of the R2 units. Patients were classified according to basic demographics, affiliation, region where treatment was provided, mechanism of injury, type of injury, time and method of transport from point of injury (POI) to R2 facility, interventions at R2, and survival. Analysis included trauma patients aged ≥18 years or older wounded in year 2008 to 2014, and treated in Afghanistan. RESULTS A total of 15,404 patients wounded and treated in R2 were included in the R2R from February 2008 to September 2014; 12,849 patients met inclusion criteria. The predominant patient affiliations included US Forces, 4,676 (36.4%); Afghan Forces, 4,549 (35.4%); and Afghan civilians, 2,178 (17.0%). Overall, battle injuries predominated (9,792 [76.2%]). Type of injury included penetrating, 7,665 (59.7%); blunt, 4,026 (31.3%); and other, 633 (4.9%). Primary mechanism of injury included explosion, 5,320 (41.4%); gunshot wounds, 3,082 (24.0%); and crash, 1,209 (9.4%). Of 12,849 patients who arrived at R2, 167 (1.3%) were dead; of 12,682 patients who were alive upon arrival, 342 (2.7%) died at R2. CONCLUSION This evaluation of the R2R describes the patient profiles of and common injuries treated in a sample of R2 facilities in Afghanistan. Ongoing and detailed analysis of R2R information may provide evidence-based guidance to military planners and medical leaders to best prepare teams and allocate R2 resources in future operations. Given the limitations of the data set, conclusions must be interpreted in context of other available data and analyses, not in isolation. LEVEL OF EVIDENCE Epidemiologic study, level IV.

Analysis of injury patterns and roles of care in US and Israel militaries during recent conflicts: Two are better than one.

BACKGROUND As new conflicts emerge and enemies evolve, military medical organizations worldwide must adopt the “lessons learned.” In this study, we describe roles of care (ROCs) deployed and injuries sustained by both US and Israeli militaries during recent conflicts. The purpose of this collaborative work is facilitate exchange of medical data among allied forces in order to advance military medicine and facilitate strategic readiness for future military engagements that may involve less predictable situations of evacuation and care, such as prolonged field care. METHODS This retrospective study was conducted for the periods of 2003 to 2014 from data retrieved from the Department of Defense Trauma Registry and the Israel Defense Force (IDF) Trauma Registry. Comparative analyses included ROC capabilities, casualties who died of wounds, as well as mechanism of injury, anatomical wound distribution, and Injury Severity Score of US and IDF casualties during recent conflicts. RESULTS Although concept of ROCs was similar among militaries, the IDF supports increased capabilities at point of injury and Role 1 including the presence of physicians, but with limited deployment of other ROCs; conversely, the US maintains fewer capabilities at Role 1 but utilized the entire spectrum of care, including extensive deployment of Roles 2/2+, during recent conflicts. Casualties from US forces (n = 19,005) and IDF (n = 2,637) exhibited significant differences in patterns of injury with higher proportions of casualties who died of wounds in the US forces (4%) compared with the IDF (0.6%). CONCLUSIONS As these data suggest deployed ROCs and injury patterns of US and Israeli militaries were both conflict and system specific. We envision that identification of discordant factors and common medical strategies of the two militaries will enable strategic readiness for future conflicts as well as foster further collaboration among allied forces with the overarching universal goal of eliminating preventable death on the battlefield.

Virologic suppression among HIV-infected US Air Force members in a highly-structured programme with free access to care.

Summary The United States Air Force HIV programme has several features that may enhance antiretroviral therapy outcomes, including free access to healthcare and mandatory clinical visits every six months at a single centre. We evaluated viral load suppression (<50 copies/ml) after 12 months of initial antiretroviral therapy, with extension to 18 and 24 months. Active duty Air Force members were categorised by year of antiretroviral therapy initiation: 2000–2005 (n = 95, 36.1%) and 2006–2011 (n = 168, 63.9%). The median months from HIV diagnosis to initial antiretroviral therapy were shorter in the 2000–2005 group (2.4, IQR 1.2–5.9) compared with the 2006–2011 group (12.6, IQR 2.6–29.0; p < 0.001). Viral load suppression was greater in the 2006–2011 group compared with the 2000–2005 group at 12 months (93.2% versus 78.6%, p = 0.002) and 18 months (91.8% versus 80.3%, p = 0.03), and trended higher at 24 months (90.8% versus 82.5%; p = 0.15). Factors associated with viral load suppression at 12 months in multivariate models included antiretroviral therapy initiation during 2006–2011 (OR 5.22, 95% CI 1.50–18.18) and CD4 count at antiretroviral therapy initiation (OR 2.29, 95% CI 1.19–14.43 per 100 cells/µl increase). Structured programmes that minimise traditional barriers to care combined with the use of contemporary antiretroviral therapy regimens can achieve clinic-wide viral load suppression in >90% of patients.

A 12-Year Analysis of Nonbattle Injury Among US Service Members Deployed to Iraq and Afghanistan

Importance Nonbattle injury (NBI) among deployed US service members increases the burden on medical systems and results in high rates of attrition, affecting the available force. The possible causes and trends of NBI in the Iraq and Afghanistan wars have, to date, not been comprehensively described. Objectives To describe NBI among service members deployed to Iraq and Afghanistan, quantify absolute numbers of NBIs and proportion of NBIs within the Department of Defense Trauma Registry, and document the characteristics of this injury category. Design, Setting, and Participants In this retrospective cohort study, data from the Department of Defense Trauma Registry on 29 958 service members injured in Iraq and Afghanistan from January 1, 2003, through December 31, 2014, were obtained. Injury incidence, patterns, and severity were characterized by battle injury and NBI. Trends in NBI were modeled using time series analysis with autoregressive integrated moving average and the weighted moving average method. Statistical analysis was performed from January 1, 2003, to December 31, 2014. Main Outcomes and Measures Primary outcomes were proportion of NBIs and the changes in NBI over time. Results Among 29 958 casualties (battle injury and NBI) analyzed, 29 003 were in men and 955 were in women; the median age at injury was 24 years (interquartile range, 21-29 years). Nonbattle injury caused 34.1% of total casualties (n = 10 203) and 11.5% of all deaths (206 of 1788). Rates of NBI were higher among women than among men (63.2% [604 of 955] vs 33.1% [9599 of 29 003]; P < .001) and in Operation New Dawn (71.0% [298 of 420]) and Operation Iraqi Freedom (36.3% [6655 of 18 334]) compared with Operation Enduring Freedom (29.0% [3250 of 11 204]) (P < .001). A higher proportion of NBIs occurred in members of the Air Force (66.3% [539 of 810]) and Navy (48.3% [394 of 815]) than in members of the Army (34.7% [7680 of 22 154]) and Marine Corps (25.7% [1584 of 6169]) (P < .001). Leading mechanisms of NBI included falls (2178 [21.3%]), motor vehicle crashes (1921 [18.8%]), machinery or equipment accidents (1283 [12.6%]), blunt objects (1107 [10.8%]), gunshot wounds (728 [7.1%]), and sports (697 [6.8%]), causing predominantly blunt trauma (7080 [69.4%]). The trend in proportion of NBIs did not decrease over time, remaining at approximately 35% (by weighted moving average) after 2006 and approximately 39% by autoregressive integrated moving average. Assuming stable battlefield conditions, the autoregressive integrated moving average model estimated that the proportion of NBIs from 2015 to 2022 would be approximately 41.0% (95% CI, 37.8%-44.3%). Conclusions and Relevance In this study, approximately one-third of injuries during the Iraq and Afghanistan wars resulted from NBI, and the proportion of NBIs was steady for 12 years. Understanding the possible causes of NBI during military operations may be useful to target protective measures and safety interventions, thereby conserving fighting strength on the battlefield.