Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Vaccination-Associated Myocarditis and Myocardial Injury.

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2.

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.

Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein. METHODS: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score. RESULTS: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055). CONCLUSIONS: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus.

BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.

Cardiotoxicity and pharmacogenetics of doxorubicin in black Zimbabwean breast cancer patients.

AIMS: Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers. METHODS: A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. Eleven per cent of the patients experienced DIC. RESULTS: The frequencies of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) were 60.7%, 17.9% and 14.3%, respectively. No association between DIC and the three variants was observed. CONCLUSIONS: This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study were different to those reported in other populations. A larger sample size with a longer follow-up time will be necessary in future studies.

HIV Infection Is Associated with Loss of Anti-Inflammatory Alveolar Macrophages.

HIV type 1 is associated with pulmonary dysfunction that is exacerbated by cigarette smoke. Alveolar macrophages (AM) are the most prominent immune cell in the alveolar space. These cells play an important role in clearing inhaled pathogens and regulating the inflammatory environment; however, how HIV infection impacts AM phenotype and function is not well understood, in part because of their autofluorescence and the absence of well-defined surface markers. The main aim of this study was to evaluate the impact of HIV infection on human AM and to compare the effect of smoking on their phenotype and function. Time-of-flight mass cytometry and RNA sequencing were used to characterize macrophages from human bronchoalveolar lavage of HIV-infected and -uninfected smokers and nonsmokers. We found that the frequency of CD163+ anti-inflammatory AM was decreased, whereas CD163-CCR7+ proinflammatory AM were increased in HIV infection. HIV-mediated proinflammatory polarization was associated with increased levels of inflammatory cytokines and macrophage activation. Conversely, smoking heightened the inflammatory response evident by change in the expression of CXCR4 and TLR4. Altogether, these findings suggest that HIV infection, along with cigarette smoke, favors a proinflammatory macrophage phenotype associated with enhanced expression of inflammatory molecules. Further, this study highlights time-of-flight mass cytometry as a reliable method for immunophenotyping the highly autofluorescent cells present in the bronchoalveolar lavage of cigarette smokers.

The Impact of Moderate or High-Intensity Combined Exercise on Systemic Inflammation Among Older Persons With and Without HIV.

BACKGROUND: We investigated whether higher-intensity exercise provided greater decrease in markers of inflammation, and whether responses differed by HIV serostatus. METHODS: People with HIV (PWH; n = 32) and controls (n = 37) aged 50-75 years completed 12 weeks moderate-intensity exercise, then were randomized to moderate- or high-intensity exercise for 12 additional weeks (n = 27 and 29, respectively). Inflammation biomarkers were measured at 0, 12, 24 weeks. Mixed and multiple regression models were adjusted for baseline inflammation, age, and body mass index. RESULTS: Baseline tumor necrosis factor-α (TNF-α), soluble TNF receptor 2 (sTNFR2), and soluble CD14 (sCD14) were significantly higher among PWH than controls (P < .04). From week 0-12, changes in interleukin-6 (IL-6), TNF-α, and sTNFR1 were not significantly different by HIV serostatus. We found no significant interaction between HIV serostatus/exercise intensity on week 12-24 changes in IL-6, TNF-α, and sTNFR1. Among high-intensity exercisers, PWH and controls had significant increases in sCD14 (P ≤ .003), controls significant increases in IL-10 (P = .01), and PWH nonsignificant decrease in highly sensitive C-reactive protein (P = .07). Other markers were not significantly different by serostatus or intensity. CONCLUSIONS: Moderate and high-intensity exercise elicited similar effects on inflammation among PWH and controls, with additional beneficial effects seen among high-intensity exercisers. Increase in sCD14 and attenuated IL-10 increase (PWH only) merit further study. CLINICAL TRIALS REGISTRATION: NCT02404792.

Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial.

BACKGROUND: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. METHODS: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. FINDINGS: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. INTERPRETATION: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.

Upregulation of Chitinase 1 in Alveolar Macrophages of HIV-Infected Smokers.

Recent studies suggest that HIV infection is an independent risk factor for the development of chronic obstructive pulmonary disease (COPD). We hypothesized that HIV infection and cigarette smoking synergize to alter the function of alveolar macrophages (AMs). To test this hypothesis, global transcriptome analysis was performed on purified AMs from 20 individuals split evenly between HIV-uninfected nonsmokers and smokers and untreated HIV-infected nonsmokers and smokers. Differential expression analysis identified 143 genes significantly altered by the combination of HIV infection and smoking. Of the differentially expressed genes, chitinase 1 (CHIT1) and cytochrome P450 family 1 subfamily B member 1 (CYP1B1), both previously associated with COPD, were among the most upregulated genes (5- and 26-fold, respectively) in the untreated HIV-infected smoker cohort compared with HIV-uninfected nonsmokers. Expression of CHIT1 and CYP1B1 correlated with the expression of genes involved in extracellular matrix organization, oxidative stress, immune response, and cell death. Using time-of-flight mass cytometry to characterize AMs, a significantly decreased expression of CD163, an M2 marker, was seen in HIV-infected subjects, and CD163 inversely correlated with CYP1B1 expression in AMs. CHIT1 protein levels were significantly upregulated in bronchoalveolar lavage fluid from HIV-infected smokers, and increased CHIT1 levels negatively correlated with lung function measurements. Overall, these findings raise the possibility that elevated CHIT1 and CYP1B1 are early indicators of COPD development in HIV-infected smokers that may serve as biomarkers for determining this risk.

Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1-Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings.

BACKGROUND: Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. METHODS: PLWH with a CD4+ count <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. RESULTS: Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. CONCLUSIONS: Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)-infected participants in resource-limited settings treated with 3 World Health Organization-recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/µL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.

Human Immunodeficiency Virus-associated Neurocognitive Impairment in Diverse Resource-limited Settings.

BACKGROUND: Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. METHODS: The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. RESULTS: Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. CONCLUSIONS: Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. CLINICAL TRIALS REGISTRATION: NCT00096824.

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial.

Background: Mild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART. Methods: Chemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response. Results: Of 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks. Conclusions: Among HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low. Clinical Trials Registration: NCT01352117.

Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study.

BACKGROUND: Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB). METHODS: Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV-infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis). RESULTS: In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin-18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87). CONCLUSION: Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation.

Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.

Background: We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States. Methods: Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates. Results: Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication. Conclusions: Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.

Herpes Simplex Virus Type 2 Acquisition Among HIV-1-Infected Adults Treated With Tenofovir Disoproxyl Fumarate as Part of Combination Antiretroviral Therapy: Results From the ACTG A5175 PEARLS Study.

Objective: Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Design: Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. Methods: HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Results: Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). Conclusions: HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

The Impact of Statin and Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy on Cognitive Function in Adults With Human Immunodeficiency Virus Infection.

BACKGROUND: Although statins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are generally well tolerated, the impact of these therapies individually or in combination on the change in neurocognitive function in persons with human immunodeficiency virus infection is unknown. METHODS: The study included participants in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort participants not receiving a statin or ACEI/ARB within 30 days of first neurologic assessment (baseline), with assessments by NPZ-3 (z score of averaged Trailmaking A and B tests and digit symbol test [DST]) from ≥2 measurements. Marginal structural models estimated the causal effect of statin or ACEI/ARB initiation on neurocognitive function; initial constant slope was assumed during the first year of treatment and a second constant slope thereafter. RESULTS: Of 3949 eligible participants, 16% started therapy with a statin, 11% with an ACEI/ARB, and 5% with both. Statin therapy had no significant effect on the composite NPZ-3 (primary outcome), Trailmaking B test, or DST. A small, nonsignificant positive effect on the Trailmaking A test was seen during year 1 (estimate, 0.088; 95% confidence interval, -.010 to .187; P = .08) and a small but significant negative effect (-0.033; -.058 to -.009; P = .007) in each subsequent year. ACEI/ARB therapy had a significant negative effect on the DST (-0.117; 95% confidence interval, -.217 to .016; P = .02) during year 1 but minimal effect in subsequent years or on other neurocognitive domains. CONCLUSIONS: In summary, although modest declines in neurocognitive performance were seen in single domains with statin or ACEI/ARB therapy, we did not find consistent evidence that statins or ACEI/ARB have an effect on global neurocognitive function. Future studies should focus on long-term neurocognitive effects.