Publications by authors named "Jason V Baker"

75 Publications

Opportunities for Re-Engaging Persons with HIV in Care at a Health Care System in Minneapolis, Minnesota.

AIDS Patient Care STDS 2022 Mar 17;36(3):83-85. Epub 2022 Feb 17.

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1089/apc.2021.0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971969PMC
March 2022

Impact of the COVID-19 pandemic on HIV testing rates across four geographically diverse urban centres in the United States: An observational study.

Lancet Reg Health Am 2022 Mar 23;7:100159. Epub 2021 Dec 23.

Department of Medicine, Brown University, Providence, RI, USA.

Background: Non-emergent clinical services were limited or suspended during the early stages of the coronavirus disease 2019 (COVID-19) pandemic in the United States (U.S.). This could adversely impact epidemics of public health importance, such as HIV, and access to testing, which is a cornerstone of prevention efforts.

Methods: In this observational study, we collected HIV testing and positivity rate clinical data from four geographically diverse U.S. healthcare systems in New Orleans, Louisiana; Minneapolis, Minnesota; Providence, Rhode Island; and, Seattle, Washington. Data from 2019 to 2020 were examined to assess changes in HIV testing in community-based, emergency department, and outpatient settings. Poisson regression was used to explore trends in HIV testing through phases of the COVID-19 pandemic.

Findings: In outpatient settings, there was a 68-97% reduction in the number of HIV tests per week during each state's stay-at-home order period, compared to during the pre-stay-at-home order period in early 2020. HIV testing remained reduced 11-54% after states transitioned to advisory phases. The HIV positivity rate increased slightly at outpatient settings, except in New Orleans where it fell.

Interpretation: We found a concerning trend of substantially decreased HIV testing across four geographically diverse sites. These findings suggest that new HIV infections within the U.S. may be undiagnosed and not yet linked to clinical care and services, as a consequence of the COVID-19 pandemic. Thus, augmented efforts to identify patients and link them to HIV services will be needed as healthcare settings return to full operation.

Funding: U.S. National Institute of Mental Health.
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http://dx.doi.org/10.1016/j.lana.2021.100159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8695134PMC
March 2022

Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial.

Ann Intern Med 2022 02 21;175(2):234-243. Epub 2021 Dec 21.

National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

Background: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.

Objective: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.

Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).

Setting: Multicenter trial.

Patients: Hospitalized patients with COVID-19 without end-organ failure.

Intervention: Bamlanivimab (7000 mg) or placebo.

Measurements: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).

Results: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs.

Limitation: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.

Conclusion: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.

Primary Funding Source: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.7326/M21-3507DOI Listing
February 2022

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3).

Clin Trials 2022 02 10;19(1):52-61. Epub 2021 Oct 10.

CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.

Background/aims: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed.

Methods: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19.

Results: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites.

Conclusion: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.
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http://dx.doi.org/10.1177/17407745211049829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847314PMC
February 2022

Acceptance of chronic pain in depressed patients with HIV: correlations with activity, functioning, and emotional distress.

AIDS Care 2021 Sep 23:1-9. Epub 2021 Sep 23.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.

Chronic pain is highly prevalent among persons with HIV (PWH), as is depression. Both comorbidities might contribute to, as well as be maintained by, avoidance-based coping. A promising alternative to avoidance-based coping is acceptance. Acceptance of pain is associated with improved functioning and quality of life in chronic pain patients, but this relationship has not been substantially explored among PWH. Cross-sectional data from 187 adult outpatients enrolled in a randomized trial for depressed PWH with chronic pain were analyzed. Controlling for pain severity and demographics, the relationships among pain acceptance and indicators of activity, functioning, and emotional distress (i.e., anxiety and anger) were assessed in seven regression models. No significant relationships were found between self-reported physical activity or objective measurement of mean steps/day with pain acceptance. Results revealed an inverse relationship between chronic pain acceptance and pain-related functional interference (b= -.52, < .01) and a positive relationship with self-reported functioning (b = 7.80,  < .01). A significant inverse relationship with anxiety symptoms (b = -1.79,  < .01) and pain acceptance was also found. Acceptance of chronic pain can facilitate decreased emotional distress, improved well-being, and better functioning and quality of life. Further investigation of chronic pain acceptance among PWH could inform the development of acceptance-based interventions.
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http://dx.doi.org/10.1080/09540121.2021.1981819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940733PMC
September 2021

Pharmacologic and Non-Pharmacologic Treatments for Chronic Pain Used by Patients with Pain, HIV, and Depression.

AIDS Behav 2022 Mar 1;26(3):864-873. Epub 2021 Sep 1.

Alpert Medical School of Brown University, Providence, RI, USA.

The objective of this study was to understand pain treatment utilization, perceived efficacy, and differences in utilization by gender, clinic site, chronicity of pain, pain severity, and depression severity among people living with HIV (PLWH), chronic pain, and elevated depression symptoms. Participants included 187 PLWH at three HIV clinics in the U.S. Overall, 85% of participants reported taking a pain medication. One quarter (25%) reported non-pharmacological professional treatments for pain (e.g., massage, physical therapy), 60% reported mind-body treatments, including exercise, meditation, and yoga, and 62% reported other non-pharmacological self-administered treatments (e.g., heat/cold). Most pain treatments were considered "slightly helpful" or "moderately helpful." Non-pharmacological self-administered treatments were more commonly used among women than men and among individuals with constant vs. intermittent pain. Further research is needed to evaluate the efficacy of the preferred analgesic modalities of PLWH.
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http://dx.doi.org/10.1007/s10461-021-03447-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125741PMC
March 2022

The Role of Inflammation and Immune Activation on Circulating Endothelial Progenitor Cells in Chronic HIV Infection.

Front Immunol 2021 17;12:663412. Epub 2021 May 17.

Department of Microbiology and Immunology. Georgetown University School of Medicine, Washington, DC, United States.

Endothelial inflammation and damage are the main drivers of cardiovascular risk/disease. Endothelial repair is mediated in part by recruitment of bone marrow endothelial progenitor/endothelial colony forming cells (EPC/ECFC). People with HIV (PWH) have increased cardiovascular risk and the impact of infection in endothelial repair is not well defined. The low frequencies and challenges to isolation and differentiation of EPC/ECFC from PBMCs had made it difficult to study their role in this context. We hypothesized that HIV driven inflammation induces phenotypic changes that reflects the impact of infection. To test this hypothesis, we evaluated expression of markers of trafficking, endothelial differentiation, and angiogenesis, and study their association with biomarkers of inflammation in a cohort of PWH. In addition, we investigated the relationship of circulating endothelial progenitors and angiogenic T cells, a T cell subset with angiogenic function. Using a flow cytometry approach, we identified two subsets of circulating progenitors LIN4CD45CD34 and LIN4CD45CD34 in PWH. We found that the phenotype but not frequencies were associated with biomarkers of inflammation. In addition, the percentage of LIN4CD45CD34 was associated with serum levels of lipids. This data may provide a new tool to better address the impact of HIV infection in endothelial inflammation and repair.
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http://dx.doi.org/10.3389/fimmu.2021.663412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165313PMC
October 2021

Short Communication: A Pilot Study of the Effects of Losartan Versus Placebo on Pneumoproteins in HIV: A Secondary Analysis of a Randomized Double Blind Study.

AIDS Res Hum Retroviruses 2022 02 30;38(2):127-130. Epub 2021 Apr 30.

Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo ( value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.
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http://dx.doi.org/10.1089/AID.2020.0285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861910PMC
February 2022

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

N Engl J Med 2021 03 22;384(10):905-914. Epub 2020 Dec 22.

From the CHIP Center of Excellence for Health, Immunity, and Infections (J.D.L., D.D.M.), and the Department of Infectious Diseases (J.D.L., D.D.M., J.-U.J.), Rigshospitalet, Copenhagen, the Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre (T.B.), the Department of Internal Medicine, Respiratory Medicine Section, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup (J.-U.J.), the Department of Infectious Diseases, Odense University Hospital, Odense (I.S.J.), and the Department of Infectious Diseases, Aarhus University Hospital, Skejby (L.Ø.) - all in Denmark; the School of Statistics (B.G.) and the Division of Biostatistics, School of Public Health (T.A.M., C.R., S.S., D.W., J.D.N.), University of Minnesota, Hennepin Healthcare Research Institute (J.V.B.), and the University of Minnesota (J.V.B.), Minneapolis; the Divisions of Pulmonary, Allergy, and Critical Care Medicine (C.E.B.) and Infectious Disease (T.L.H.), Department of Medicine, Duke University, Durham, and the Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy, and Immunology, Wake Forest School of Medicine, Winston-Salem (D.C.F.) - both in North Carolina; the Center for Advanced Heart and Lung Disease (R.L.G.) and the Division of Infectious Diseases (U.S.), Baylor University Medical Center, and the Department of Internal Medicine, UT Southwestern Medical Center (M.K.J.), Dallas; the Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray (S.M.B.), and the Department of Internal Medicine, University of Utah (S.M.B., E.S.H.) and Intermountain Healthcare (K.U.K.), Salt Lake City - both in Utah; the Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville (W.H.S.); the Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles (M.E.B.), the Department of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco (M.A.M.), and Gilead Sciences, Foster City (H.C.) - all in California; the Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta (B.G.L.); Denver Public Health, Denver Health and Hospital Authority, Denver (E.M.G.), and the Department of Emergency Medicine, University of Colorado School of Medicine, Aurora (A.A.G.); the Department of Infectious Diseases, Henry Ford Hospital, Detroit (N.M.); the Kirby Institute, University of New South Wales (C.C.C., M.N.P.), and St. Vincent's Hospital (M.N.P.), Sydney; the Department of Veterans Affairs (V.J.D.), the Veterans Affairs Medical Center (V.L.K.), and George Washington University School of Medicine and Health Sciences (V.L.K.), Washington, DC; the Medical Research Council Clinical Trials Unit at UCL (A.G., A.G.B., M.K.B.P.), the Institute of Clinical Trials and Methodology (M.K.B.P.), and the Institute for Global Health (A.N.P.), University College London, and Guy's and St. Thomas' NHS Foundation Trust (A.G.), London; the National Institute of Allergy and Infectious Diseases, Bethesda (E.S.H., H.C.L.), and Leidos Biomedical Research, Frederick (R.L.D., M.T.) - both in Maryland; the Infectious Diseases Department and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (R.P.); Eli Lilly, Indianapolis (P.K.); the Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (A.C.G.); and the Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston (B.T.T.).

Background: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

Methods: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

Results: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

Conclusions: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
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http://dx.doi.org/10.1056/NEJMoa2033130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781100PMC
March 2021

Losartan to reduce inflammation and fibrosis endpoints in HIV disease.

AIDS 2021 03;35(4):575-583

University of Vermont, Burlington, Vermont, USA.

Background: Persistent inflammation and incomplete immune recovery among persons with HIV (PHIV) are associated with increased disease risk. We hypothesized that the angiotensin receptor blocker (ARB) losartan would reduce inflammation by mitigating nuclear factor (NF)κB responses and promote T-cell recovery via inhibition of transforming growth factor-beta (TGFβ)-mediated fibrosis.

Methods: Losartan (100 mg) versus placebo over 12 months was investigated in a randomized (1 : 1) placebo-controlled trial, among PHIV age at least 50 years, receiving antiretroviral therapy (ART), with HIV RNA less than 200 copies/ml and CD4+ cell count 600 cells/μl or less. Inflammation, fibrosis and myocardial biomarkers were measured in blood using ELISA, electrochemiluminescence and immunoturbidimetric methods, and T-cell and monocyte phenotypes were assessed with flow cytometry among a subset of participants. Changes over follow-up in (log-2 transformed) biomarkers and cell phenotypes (untransformed) were compared between losartan and placebo arms using linear mixed models.

Results: Among 108 PHIV (n = 52 to losartan; n = 56 to placebo), 97% had a month 12 visit. Median age was 57 years and baseline CD4+ cell count was 408 cells/μl. Losartan treatment was not associated with an improvement in interleukin-6 levels, or other blood measures of inflammation, immune activation, fibrosis activity or myocardial function. CD4+ and CD8+ T cells also did not differ by treatment group. Losartan reduced SBP and DBP by 6 and 5 mmHg, respectively.

Conclusion: Among older PHIV with viral suppression, losartan did not improve blood measures of inflammation nor T-cell immune recovery. Losartan treatment is unlikely to reduce inflammation associated comorbidities to a clinically meaningful degree, beyond the benefits from lowering blood pressure.

Clinicaltrialsgov: NCT02049307.
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http://dx.doi.org/10.1097/QAD.0000000000002773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062089PMC
March 2021

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3).

medRxiv 2021 Apr 8. Epub 2021 Apr 8.

CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.

Background: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership initiated the Therapeutics for Inpatients with COVID-19 (TICO). TICO is a multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. Four agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed.

Protocol Design And Implementation: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. TICO utilizes a MAMS design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo as well as the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and DSMB schedule was developed for the study of agents with limited in-human data.

Challenges: Challenges included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff, and obtaining regulatory approvals across a global network of sites.

Conclusion: Through a robust multi-network partnership, the TICO protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required.
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http://dx.doi.org/10.1101/2020.11.08.20227876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675662PMC
April 2021

Developing an Ethics Framework for Allocating Remdesivir in the COVID-19 Pandemic.

Mayo Clin Proc 2020 09 20;95(9):1946-1954. Epub 2020 Jun 20.

University of Minnesota, Minneapolis. Electronic address:

On May 1, 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to allow use of the antiviral drug remdesivir to treat patients with severe coronavirus disease-2019 (COVID-19). Remdesivir is an investigational drug studied in clinical trials for COVID-19 and is available to children and pregnant women through compassionate-use access but is not yet FDA approved. In early May, the US Department of Health and Human Services began to distribute remdesivir, donated by Gilead Sciences, Inc., to hospitals and state health departments for emergency use; multiple shipments have since been distributed. This process has raised questions of how remdesivir should be allocated. The Minnesota Department of Health has collaborated with the Minnesota COVID Ethics Collaborative and multiple clinical experts to issue an Ethical Framework for May 2020 Allocation of Remdesivir in the COVID-19 Pandemic. The framework builds on extensive ethical guidance developed for public health emergencies in Minnesota before the COVID-19 crisis. The Minnesota remdesivir allocation framework specifies an ethical approach to distributing the drug to facilities across the state and then among COVID-19 patients within each facility. This article describes the process of developing the framework and adjustments in the framework over time with emergence of new data, analyzes key issues addressed, and suggests next steps. Sharing this framework and the development process can encourage transparency and may be useful to other states formulating and refining their approach to remdesivir EUA allocation.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305893PMC
September 2020

The Current State of HIV and Aging: Findings Presented at the 10th International Workshop on HIV and Aging.

AIDS Res Hum Retroviruses 2020 12 23;36(12):973-981. Epub 2020 Sep 23.

Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.

With increasing effectiveness of antiretroviral therapy, people with HIV (PWH) are living longer and the prevalence of older PWH continues to increase. Accordingly, PWH are experiencing an increased burden of age-related comorbidities. With this shifting demographics, clinicians and researchers face additional challenges in how to identify, address, and manage the complex intersections of HIV- and aging-related conditions. Established in 2009, the International Workshop on HIV and Aging brings together clinicians and researchers in cross-disciplinary fields along with community advocates and PWH to address the multidisciplinary nature of HIV and aging. This article summarizes plenary talks from the 10th Annual International Workshop on HIV and Aging, which took place in New York City on October 10 and 11, 2019. Presentation topics included the following: the burdens of HIV-associated comorbidities, aging phenotypes, community engagement, and loneliness; these issues are especially important for older PWH, considering the current COVID-19 pandemic. We also discuss broad questions and potential directions for future research necessary to better understand the interaction between HIV and aging.
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http://dx.doi.org/10.1089/AID.2020.0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703090PMC
December 2020

Elevated N-terminal prohormone of brain natriuretic peptide among persons living with HIV in a South African peri-urban township.

ESC Heart Fail 2020 10 25;7(5):3246-3251. Epub 2020 Jun 25.

Department of Medicine, University of Cape Town, Cape Town, South Africa.

Aims: Efforts to improve access to antiretroviral therapy (ART) have shifted morbidity and mortality among persons living with HIV (PLWH) from AIDS to non-communicable diseases, such as cardiovascular disease (CVD). However, contemporary data on CVD among PLWH in sub-Saharan Africa in the current ART era are lacking. The aim of this study was to assess the burden of cardiac stress among PLWH in South Africa via measurement of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

Methods And Results: NT-proBNP was measured at baseline in 224 PLWH enrolled in a sub-study of a tuberculosis vaccine trial in Khayelitsha township near Cape Town, South Africa. Thresholds were applied at the assay's limit of detection (≥137 pg/mL) and a level indicative of symptomatic heart failure in the acute setting (>300 pg/mL). Mean (SD) age of participants was 39 (6) years, 86% were female, and 19% were hypertensive. Mean (SD) duration of HIV diagnosis was 8.3 (3.9) years and CD4 + count was 673 (267) with 79% prescribed ART for a duration of 5.6 (2.7) years. Thirty-one percent of participants had NT-proBNP > 300 pg/mL. Elevated vs. undetectable NT-proBNP level was associated with older age (P = 0.04), no ART (P = 0.03), and higher plasma tumour necrosis factor-α (P = 0.01).

Conclusions: Among South African PLWH largely free of known CVD and on ART with high CD4 + counts and few comorbidities, we observed a high proportion with elevated NT-proBNP levels, suggesting the burden of cardiac stress in this population may be high. This observation underscores the need for more in-depth research, including the current effect of HIV on heart failure risk among a growing ART-treated population in sub-Saharan Africa.
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http://dx.doi.org/10.1002/ehf2.12849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524119PMC
October 2020

The Lymphoid Tissue Pharmacokinetics of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide in HIV-Infected Persons.

Clin Pharmacol Ther 2020 11 11;108(5):971-975. Epub 2020 Jun 11.

Division of Infectious Diseases, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

The secondary lymphoid tissues (LT), lymph nodes (LN) and gut-associated lymphoid tissue are the primary sites of HIV replication and where the latent pool of virus is maintained. We compared the pharmacokinetics of tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) in LT of 13 HIV-infected persons receiving a TDF-containing antiretroviral regimen who subsequently switched to a TAF-containing regimen. Study participants were on stable antiretroviral therapy for ≥12 months with plasma HIV-RNA < 48 copies/mL for 6 months before enrollment and entry CD4 cell counts > 300 cells/µL. Intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) were quantified in PBMCs and in mononuclear cells obtained from LN, ileum and rectal tissues. With TAF, the TFV-DP concentrations in PBMCs and LN were 7.3-fold and 6.4-fold higher (ratios of geometric means of TAF to TDF), respectively, compared with TDF; ileal and rectal concentrations, however, were lower with geometric mean ratios of 0.14 and 0.18, respectively. A statistically significant relationship was observed between PBMC and LN concentrations of TFV-DP. During TDF-containing therapy, the expected effect of cobicistat to increase TFV plasma concentrations was observed, as were higher TFV-DP concentrations in PBMCs and mononuclear cells from LN, ileum and rectal tissues. The higher TFV-DP concentrations achieved with TAF in the LN provides the first human correlate of the observation in animals that TAF produced higher tenofovir LN concentrations. The ability to increase LN concentrations allows investigations of whether antiretroviral regimens with improved LN pharmacokinetics elicit a more complete virologic response in that compartment.
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http://dx.doi.org/10.1002/cpt.1883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935460PMC
November 2020

Factor Xa Inhibition Reduces Coagulation Activity but Not Inflammation Among People With HIV: A Randomized Clinical Trial.

Open Forum Infect Dis 2020 Feb 1;7(2):ofaa026. Epub 2020 Feb 1.

University of Vermont, Burlington, Vermont, USA.

Background: Coagulation activity among persons with HIV is associated with end-organ disease risk, but the pathogenesis is not well characterized. We tested a hypothesis that hypercoagulation contributes to disease risk, in part, via upregulation of inflammation.

Methods: Treatment effects of edoxaban (30 mg), a direct factor Xa inhibitor, vs placebo were investigated in a randomized, double-blind crossover trial among participants with HIV and viral suppression and D-dimer levels ≥100 ng/mL. During each 4-month crossover period, blood measures of coagulation, inflammation, and immune activation were assessed. Analyses of change on edoxaban vs change on placebo used linear mixed models.

Results: Forty-four participants were randomized, and 40 completed at least 1 visit during each study period. The mean age was 49 years, and the CD4+ count was 739 cells/mm. Edoxaban treatment led to declines in D-dimer (44%) and thrombin-antithrombin complex (26%) but did not lower inflammatory or immune activation measures. More bruising or bleeding events occurred during edoxaban (n = 28) than during placebo or no drug periods (n = 15).

Conclusions: The direct factor Xa inhibitor edoxaban led to a substantial reduction in coagulation but no effect on inflammation or immune activation. These results do not support that hypercoagulation contributes to ongoing inflammation during chronic antiretroviral therapy-treated HIV disease.
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http://dx.doi.org/10.1093/ofid/ofaa026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008475PMC
February 2020

Role of Inflammatory Biomarkers in the Prevalence and Incidence of Hypertension Among HIV-Positive Participants in the START Trial.

Am J Hypertens 2020 01;33(1):43-52

Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

Background: The association between hypertension (HTN) and inflammatory biomarkers (interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) in HIV-positive persons with CD4+ count >500 cells/mm3 is unknown.

Methods: We studied HTN in participants of the Strategic Timing of AntiRetroviral Treatment (START) trial of immediate vs. deferred antiretroviral therapy (ART) in HIV-positive, ART naive adults with CD4+ count > 500 cells/mm3. HTN was defined as having a systolic blood pressure (BP) ≥140 mmHg, a diastolic BP ≥90 mmHg, or using BP-lowering therapy. Logistic and discrete Cox regression models were used to study the association between baseline biomarker levels with prevalent and incident HTN.

Results: Among 4,249 participants with no history of cardiovascular disease, the median age was 36 years, 55% were nonwhite, and the prevalence of HTN at baseline was 18.9%. After adjustment for race, age, gender, body mass index (BMI), diabetes, smoking, HIV RNA and CD4+ levels, associations of IL-6 and hsCRP with HTN prevalence were not significant (OR per twofold higher:1.10, 95% confidence interval [CI]: 0.99, 1.20 for IL-6 and 1.05, 95% CI: 0.99, 1.10 for hsCRP). Overall incidence of HTN was 6.8 cases/100 person years. In similarly adjusted models, neither IL-6 (Hazard ratios [HR] per twofold higher IL-6 levels: 0.97, 95% CI: 0.88, 1.08) nor hsCRP (HR per twofold higher hsCRP levels: 0.97, 95% CI: 0.92, 1.02) were associated with risk of incident HTN. Associations did not differ by treatment group. Age, race, gender, and BMI were significantly associated with both the prevalence and incidence of HTN.

Conclusions: Traditional risk factors and not baseline levels of IL-6 or hsCRP were associated with the prevalence and incidence of HTN in START.
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http://dx.doi.org/10.1093/ajh/hpz132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931895PMC
January 2020

A Pilot Study of a Mobile App to Support HIV Antiretroviral Therapy Adherence Among Men Who Have Sex with Men Who Use Stimulants.

AIDS Behav 2019 Nov;23(11):3184-3198

School of Medicine, University of Miami, Coral Gables, USA.

APP+ is a theoretically-grounded mobile app intervention to improve antiretroviral (ART) adherence among men who have sex with men (MSM) who use stimulants. We assessed the feasibility and acceptability of APP+ in a six-month randomized controlled trial among a national sample of 90 MSM recruited online; secondarily, we examined changes in self-reported ART adherence by study arm. Retention at the final assessment was 82%, and acceptability ratings were comparable to other technology-based interventions. MSM in the APP+ group reported higher self-reported percentage ART adherence in the past 30 days at the four-month timepoint compared to a no-treatment control group (89.0% vs. 77.2%). However, once access to the app was removed after month four, group differences in ART adherence diminished by month six. APP+ may be a potentially promising intervention approach for MSM living with HIV who use stimulants but would require enhancements to optimize acceptability and demonstrate more sustained effects.
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http://dx.doi.org/10.1007/s10461-019-02597-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803067PMC
November 2019

Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study.

J Int AIDS Soc 2019 06;22(6):e25297

Denver Health Medical Center, Denver, CO, USA.

Introduction: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study.

Methods: Plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein, serum amyloid A protein (SAA), IL-27, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, D-dimer and the CD4+/CD8+ T-cell ratio, were analysed at baseline and eight months after ART initiation in treatment-naïve participants with HIV and CD4+ T-cells >500 cells/mm enrolled in the immediate arm of START. Adherence was assessed by seven-day self-report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight-month visit in participants who achieved virologic suppression (<50 copies/mL).

Results: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight-month visit in the period between 2009 and 2013. Median (IQR) CD4+ T-cell count before ART was 651 (585, 769) cells/mm . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL-6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed.

Conclusions: Incomplete ART adherence was associated with higher IL-6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.
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http://dx.doi.org/10.1002/jia2.25297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597899PMC
June 2019

Concordance of Self- and Clinician-Collected Anal Swabs to Detect Human Papillomavirus in a Sample of HIV-Negative Men.

J Low Genit Tract Dis 2019 Jul;23(3):200-204

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.

Objective: The aim of this study was to determine the concordance of self- and clinician-collected anorectal swabs for the detection of human papillomavirus (HPV) DNA in a population of HIV-negative men who have sex with men (MSM).

Methods: This cross-sectional study involved recruitment of HIV-negative MSM in a Midwestern US metropolitan area to collect paired sequential self- and clinician-collected anorectal swabs using illustrated instructions. Swabs were tested for type-specific HPV DNA with a comparison of type-specific HPV categories detected by each method. The sensitivity and specificity of self-collection were calculated assuming clinician collection as the criterion standard. McNemar's test and κ statistics were used to determine percent agreement and concordance of self- and clinician-collected swab results.

Results: Seventy-eight participants had paired anorectal swab samples of adequate quality for analyses. The sensitivity and specificity of self-collected swabs for detection of all high-risk HPV DNA types were 69.8% and 91.4%, respectively. Similar degrees of sensitivity and specificity of self-collection were seen for other groups of high-risk HPV types. Percent agreement and κ statistic for self- and clinician-collected swabs for all high-risk HPV types were 80.8% and 0.53, respectively.

Conclusions: Self-collected anorectal swab samples showed lower sensitivity but moderate to high specificity for detection of high-risk and vaccine-preventable HPV types compared with clinician-collected swab samples. Self-collection instructional details and the thoroughness of clinician collection of samples may have impacted sensitivity and specificity, suggesting a need to optimize and standardize instructions.
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http://dx.doi.org/10.1097/LGT.0000000000000475DOI Listing
July 2019

The Effects of Recombinant Human Lactoferrin on Immune Activation and the Intestinal Microbiome Among Persons Living with Human Immunodeficiency Virus and Receiving Antiretroviral Therapy.

J Infect Dis 2019 05;219(12):1963-1968

Leidos Biomedical Research, Frederick, Maryland.

Lactoferrin modulates mucosal immunity and targets mechanisms contributing to inflammation during human immunodeficiency virus disease. A randomized placebo-controlled crossover clinical trial of recombinant human (rh) lactoferrin was conducted among 54 human immunodeficiency virus-infected participants with viral suppression. Outcomes were tolerability, inflammatory, and immunologic measures, and the intestinal microbiome. The median age was 51 years, and the median CD4+ cell count was 651/µL. Adherence and adverse events did not differ between rh-lactoferrin and placebo. There was no significant effect on plasma interleukin-6 or D-dimer levels, nor on monocyte/T-cell activation, mucosal integrity, or intestinal microbiota diversity. Oral administration of rh-lactoferrin was safe but did not reduce inflammation and immune activation. Clinical Trials Registration: NCT01830595.
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http://dx.doi.org/10.1093/infdis/jiz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784498PMC
May 2019

Risk Factors for Low CD4+ Count Recovery Despite Viral Suppression Among Participants Initiating Antiretroviral Treatment With CD4+ Counts > 500 Cells/mm3: Findings From the Strategic Timing of AntiRetroviral Therapy (START) Trial.

J Acquir Immune Defic Syndr 2019 05;81(1):10-17

University of Minnesota, Minneapolis, MN.

Background: Low CD4 recovery among HIV-positive individuals who achieve virologic suppression is common but has not been studied among individuals initiating treatment at CD4 counts of >500 cells/mm.

Setting: United States, Africa, Asia, Europe and Israel, Australia, Latin America.

Methods: Among participants randomized to immediate antiretroviral therapy (ART) in the Strategic Timing of AntiRetroviral Therapy trial, low CD4 recovery was defined as a CD4 increase of <50 cells/mm from baseline after 8 months despite viral load of ≤200 copies/mL. Risk factors for low recovery were investigated with logistic regression.

Results: Low CD4 recovery was observed in 39.7% of participants. Male sex [odds ratio (OR), 1.53; P = 0.007], lower screening CD4 cell counts (OR, 1.09 per 100 fewer cells/mm; P = 0.004), higher baseline CD8 cell counts (OR, 1.05 per 100 more cells/mm; P < 0.001), and lower HIV RNA levels (OR, 1.93 per log10 decrease; P < 0.001) were associated with low CD4 recovery. D-dimer had a quadratic association with low CD4 recovery, with lowest odds occurring at 0.32 μg/mL. At lower HIV RNA levels, the odds of low CD4 recovery were elevated across the levels of screening CD4 count; but at higher HIV RNA levels, the odds of low CD4 recovery were higher among those with lower vs. higher screening CD4.

Conclusions: Low CD4 recovery is frequent among participants starting ART at high CD4 counts. Risk factors include male sex, lower screening CD4 cell counts, higher CD8 cell counts, and lower HIV RNA levels. More follow-up is required to determine the impact of low CD4 recovery on clinical outcomes.
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http://dx.doi.org/10.1097/QAI.0000000000001967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456414PMC
May 2019

Associations between baseline biomarkers and lung function in HIV-positive individuals.

AIDS 2019 03;33(4):655-664

Minneapolis VA Health Care System.

Objective: The aim of this study was to analyse the association of baseline biomarker data with cross-sectional lung function and subsequent decline in lung function in HIV-positive persons.

Design: Lung function was modelled in all START pulmonary substudy participants who had baseline biomarker data and good-quality spirometry. In longitudinal analyses, we restricted to those participants with at least one good-quality follow-up spirometry test.

Methods: We performed linear regression of baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC and their longitudinal slopes on log2-transformed baseline biomarkers with adjustment for age, sex, race, region, smoking status, baseline CD4+ T-cell counts and baseline HIV-RNA. Biomarkers included D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-27, serum amyloid A, soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1, albumin and total bilirubin.

Results: Among 903 included participants, baseline median age was 36 years, CD4+ cell count was 647 cells/μl, and 28.5% were current smokers. In adjusted analyses, elevated markers of systemic inflammation (hsCRP, IL-6 and serum amyloid A) were associated with lower baseline FEV1 and FVC. Elevated D-dimer and IL-6 were associated with worse airflow obstruction (lower FEV1/FVC). Despite these cross-sectional associations at baseline, no associations were found between baseline biomarkers and subsequent longitudinal lung function decline over a median follow-up time of 3.9 years (3293 spirometry-years of follow-up).

Conclusion: Commonly available biomarkers, in particular markers of systemic inflammation, are associated with worse cross-sectional lung function, but do not associate with subsequent lung function decline among HIV-positive persons with early HIV infection and baseline CD4 T-cell counts more than 500 cells/μl.
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http://dx.doi.org/10.1097/QAD.0000000000002101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399058PMC
March 2019

Assessing inflammation and its role in comorbidities among persons living with HIV.

Curr Opin Infect Dis 2019 02;32(1):8-15

Department of Medicine, University of Minnesota.

Purpose Of Review: This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART).

Recent Findings: We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways.

Summary: Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4 T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH.
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http://dx.doi.org/10.1097/QCO.0000000000000510DOI Listing
February 2019

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus.

Res Pract Thromb Haemost 2018 Oct 11;2(4):708-717. Epub 2018 Sep 11.

Department of Medicine University of Minnesota Minneapolis Minnesota USA.

Background: Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non-AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro- and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.

Methods: In a nested case-control study of HIV+ individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non-violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue-factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F)II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor, and protein C (PC) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve (AUC).

Results: Levels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls (<0.05 for all).

Conclusions: Antithrombin, FV, FVIII, and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro- and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.
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http://dx.doi.org/10.1002/rth2.12147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178732PMC
October 2018

Inflammation Associates With Impaired Small Arterial Elasticity Early in HIV Disease.

Open Forum Infect Dis 2018 Jun 19;5(6):ofy117. Epub 2018 May 19.

Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

We estimated small arterial elasticity and used linear regression to evaluate its association with inflammatory biomarkers among antiretroviral therapy-naïve, HIV-positive patients with high CD4+ counts. After adjustment, high-sensitivity C-reactive protein and interleukin-6 were inversely associated with small arterial elasticity. These data suggest that systemic inflammation may contribute to vascular dysfunction even in very early HIV disease.
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http://dx.doi.org/10.1093/ofid/ofy117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007791PMC
June 2018

HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome.

J Virol 2018 07 13;92(13). Epub 2018 Jun 13.

Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner. The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.
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http://dx.doi.org/10.1128/JVI.00037-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002723PMC
July 2018

Systemic Inflammation, Coagulation, and Clinical Risk in the START Trial.

Open Forum Infect Dis 2017 28;4(4):ofx262. Epub 2017 Nov 28.

National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, Maryland.

Background: The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation.

Methods: Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry.

Results: Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%.

Conclusions: These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.
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http://dx.doi.org/10.1093/ofid/ofx262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751061PMC
November 2017

Serum Albumin as a Prognostic Marker for Serious Non-AIDS Endpoints in the Strategic Timing of Antiretroviral Treatment (START) Study.

J Infect Dis 2018 01;217(3):405-412

Research Department of Infection and Population Health, University College London Medical School, United Kingdom.

Background: Serum albumin may be used to stratify human immunodeficiency virus (HIV)-infected persons with high CD4 count according to their risk of serious non-AIDS endpoints.

Methods: Cox proportional hazards models were used to analyze the risk of serious non-AIDS events in the Strategic Timing of Antiretroviral Treatment (START) study (NCT00867048) with serum albumin as a fixed and time-updated predictor. Models with exclusion of events during initial follow-up years were built to assess the ability of serum albumin to predict beyond shorter periods of time. Secondarily, we considered hospitalizations and AIDS events.

Results: Among 4576 participants, 71 developed a serious non-AIDS event, 788 were hospitalized, and 63 experienced an AIDS event. After adjusting for a range of variables associated with hypoalbuminemia, higher baseline serum albumin (per 1 g/dL) was associated with a decreased risk of serious non-AIDS events (hazard ratio, 0.37 [95% confidence interval, .20-.71]; P = .002). Similar results were obtained in a time-updated model, after controlling for interleukin 6, and after excluding initial follow-up years. Serum albumin was independently associated with hospitalization but not with risk of AIDS.

Conclusions: A low serum albumin level is a predictor for short- and long-term serious non-AIDS events, and may be a useful marker of risk of noncommunicable diseases, particularly in resource-limited settings.
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http://dx.doi.org/10.1093/infdis/jix350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853310PMC
January 2018
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