Publications by authors named "Birgit Grund"

37 Publications

Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery.

Am J Respir Crit Care Med 2022 May 17. Epub 2022 May 17.

University of Colorado Denver School of Medicine, 12225, Department of Emergency Medicine, Aurora, Colorado, United States;

Rationale: Uncertainty regarding the natural history of coronavirus disease 2019 (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized COVID-19 patients.

Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19 comparing three distinct definitions of recovery.

Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach 2) the Therapeutics for Inpatients with COVID-19 (TICO) trials "sustained recovery" approach, and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-intensive care unit setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery.

Measurements And Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age 68 vs. 59 years; p<0.001) and more had a comorbidity (84% vs. 70%; p<0.001). Of 170 discordant participants, 106 (62%) had post-discharge events captured by the TICO approach.

Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant post-discharge events within 90 days after randomization, in patients that would be considered "recovered" using the hospital discharge approach. Employing the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should employ follow-up times up to 90 days to assess clinical recovery more accurately.
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http://dx.doi.org/10.1164/rccm.202112-2836OCDOI Listing
May 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

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

Ann Intern Med 2021 08 15;174(8):1151-1158. Epub 2021 Jun 15.

National Institutes of Health, Bethesda, Maryland (K.S., A.K.P., H.C.L., H.M.).

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.
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http://dx.doi.org/10.7326/M21-1647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252833PMC
August 2021

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

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

Health Utility Estimates and Their Application to HIV Prevention in the United States: Implications for Cost-Effectiveness Modeling and Future Research Needs.

MDM Policy Pract 2020 Jul-Dec;5(2):2381468320936219. Epub 2020 Aug 1.

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.

Health utility estimates from the current era of HIV treatment, critical for cost-effectiveness analyses (CEA) informing HIV health policy, are limited. We examined peer-reviewed literature to assess the appropriateness of commonly referenced utilities, present previously unreported quality-of-life data from two studies, and discuss future implications for HIV-related CEA. We searched a database of cost-effectiveness analyses specific to HIV prevention efforts from 1999 to 2016 to identify the most commonly referenced sources for health utilities and to examine practices around using and reporting health utility data. Additionally, we present new utility estimates from the Centers of Disease Control and Prevention's Medical Monitoring Project (MMP) and the INSIGHT Strategies for Management of Anti-Retroviral Therapy (SMART) trial. We compare data collection time frames, sample characteristics, assessment methods, and key estimates. Data collection for the most frequently cited utility estimates ranged from 1985 to 1997, predating modern HIV treatment. Reporting practices around utility weights are poor and lack details on participant characteristics, which may be important stratifying factors for CEA. More recent utility estimates derived from MMP and SMART were similar across CD4+ count strata and had a narrower range than pre-antiretroviral therapy (ART) utilities. Despite the widespread use of ART, cost-effectiveness analysis of HIV prevention interventions frequently apply pre-ART health utility weights. Use of utility weights reflecting the current state of the US epidemic are needed to best inform HIV research and public policy decisions. Improved practices around the selection, application, and reporting of health utility data used in HIV prevention CEA are needed to improve transparency.
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http://dx.doi.org/10.1177/2381468320936219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432967PMC
August 2020

Interim monitoring in a treatment strategy trial with a composite primary endpoint.

Contemp Clin Trials 2019 11 11;86:105846. Epub 2019 Sep 11.

School of Medicine, University of California, San Francisco, CA, USA.

When a clinical trial has a composite endpoint and a comparison of treatment strategies with multiple intervention components, interim data reviews by a data safety and monitoring board (DSMB) can be challenging as the data evolve on multiple fronts. We illustrate with a study in the treatment of Kaposi sarcoma (KS), an HIV-associated cancer with a multi-faceted disease presentation. The study, ACTG-A5264/AMC-067, was a 1:1 randomized trial to compare two strategies: immediate initiation of etoposide with antiretroviral therapy (ART), or ART with delayed etoposide upon disease progression. The outcome was a composite endpoint that included the following events, ordered from worst to best in the following three categories: (1) KS progression at 48 weeks, death, initiation of alternate KS treatment, loss to study follow-up; (2) stable KS; and (3) partial or complete KS response at 48 weeks. We present the interim results on the composite endpoint and the individual components, where components favored different study arms at an interim review. To facilitate interim data monitoring for complex trials, we recommend clear communications between the study team and the DSMB prior to the initiation of the trial on the need for a composite endpoint, the intentions behind the defined strategies, and relative importance of individual components of the composite endpoint. We also recommend flexibility in the timing of data reviews by the DSMB to interpret emerging data in multiple dimensions. Clinicaltrials.govNCT01352117.
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http://dx.doi.org/10.1016/j.cct.2019.105846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854316PMC
November 2019

Prioritisation of subgroups for immediate antiretroviral therapy - Authors' reply.

Lancet HIV 2018 05 1;5(5):e206. Epub 2018 May 1.

University of Minnesota, School of Statistics, Minneapolis, MN, USA.

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http://dx.doi.org/10.1016/S2352-3018(18)30060-2DOI Listing
May 2018

How to construct an optimal interim report: What the data monitoring committee does and doesn't need to know.

Clin Trials 2018 08 18;15(4):359-365. Epub 2018 Mar 18.

1 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Background: Data monitoring committees for randomized clinical trials have the responsibility of safeguarding interests of trial participants. To do so, the data monitoring committee must receive reports on safety and efficacy to assess risk/benefit and on trial conduct to ensure that the study can achieve its goals. This article outlines the key components of reports to the data monitoring committee and the important role of the unblinded statistician in preparing those reports.

Methods: Most data monitoring committee meetings include open and closed sessions. For each session, there is a report of interim results. The open session is attended by the sponsor and lead investigators, including the statistician(s) responsible for the trial design. These investigators are blinded to the interim treatment comparisons. The closed session is attended by the data monitoring committee members and by the statistician(s) who prepared the closed report. These individuals are unblinded to interim treatment comparisons and therefore are not involved in study design changes. The optimal content of data monitoring committee reports and qualifications of the unblinded statistician(s) are discussed.

Reports: Open reports should include responses to data monitoring committee recommendations, a synopsis of the protocol, a review of the protocol history and amendments, and information on enrollment, baseline characteristics, completeness of follow-up, and data quality. The open report is also a vehicle through which the sponsor and investigators should inform the data monitoring committee of relevant external information. Data in the open report are pooled over the treatment groups. The open report should not include data summaries by treatment group. The closed report should include a written summary with references to key tables and figures and methods used to prepare them. Tables and figures should summarize baseline characteristics, follow-up completeness, treatment adherence, and major safety and efficacy outcomes by treatment group. Text summaries should accompany the tables and figures. The data monitoring committee monitoring history (e.g. treatment differences at previous meetings) should be summarized. The unblinded statistician preparing the closed report should be familiar with the protocol and data collection plan and be capable of customizing the report to the current stage of the trial. This includes anticipating questions that may arise during the data monitoring committee review and pro-actively including data summaries to address these questions.

Conclusions: There is considerable variation in the quality of open and closed data monitoring committee reports. Open and closed data monitoring committee reports should be concise, up to date, and informative. To achieve this, unblinded statisticians responsible for preparing closed data monitoring committee reports should be familiar with the statistical methods, the trial protocol, and the data collection plan. They should be capable of anticipating questions from the data monitoring committee and responding to requests for additional analyses.
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http://dx.doi.org/10.1177/1740774518764449DOI Listing
August 2018

How to construct an optimal interim report: What the data monitoring committee does and doesn't need to know.

Clin Trials 2018 08 18;15(4):359-365. Epub 2018 Mar 18.

1 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Background: Data monitoring committees for randomized clinical trials have the responsibility of safeguarding interests of trial participants. To do so, the data monitoring committee must receive reports on safety and efficacy to assess risk/benefit and on trial conduct to ensure that the study can achieve its goals. This article outlines the key components of reports to the data monitoring committee and the important role of the unblinded statistician in preparing those reports.

Methods: Most data monitoring committee meetings include open and closed sessions. For each session, there is a report of interim results. The open session is attended by the sponsor and lead investigators, including the statistician(s) responsible for the trial design. These investigators are blinded to the interim treatment comparisons. The closed session is attended by the data monitoring committee members and by the statistician(s) who prepared the closed report. These individuals are unblinded to interim treatment comparisons and therefore are not involved in study design changes. The optimal content of data monitoring committee reports and qualifications of the unblinded statistician(s) are discussed.

Reports: Open reports should include responses to data monitoring committee recommendations, a synopsis of the protocol, a review of the protocol history and amendments, and information on enrollment, baseline characteristics, completeness of follow-up, and data quality. The open report is also a vehicle through which the sponsor and investigators should inform the data monitoring committee of relevant external information. Data in the open report are pooled over the treatment groups. The open report should not include data summaries by treatment group. The closed report should include a written summary with references to key tables and figures and methods used to prepare them. Tables and figures should summarize baseline characteristics, follow-up completeness, treatment adherence, and major safety and efficacy outcomes by treatment group. Text summaries should accompany the tables and figures. The data monitoring committee monitoring history (e.g. treatment differences at previous meetings) should be summarized. The unblinded statistician preparing the closed report should be familiar with the protocol and data collection plan and be capable of customizing the report to the current stage of the trial. This includes anticipating questions that may arise during the data monitoring committee review and pro-actively including data summaries to address these questions.

Conclusions: There is considerable variation in the quality of open and closed data monitoring committee reports. Open and closed data monitoring committee reports should be concise, up to date, and informative. To achieve this, unblinded statisticians responsible for preparing closed data monitoring committee reports should be familiar with the statistical methods, the trial protocol, and the data collection plan. They should be capable of anticipating questions from the data monitoring committee and responding to requests for additional analyses.
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http://dx.doi.org/10.1177/1740774518764449DOI Listing
August 2018

No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts.

AIDS 2018 05;32(8):985-997

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Objective: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl.

Design: Randomized trial.

Methods: The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/μl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models.

Results: The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/μl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P < 0.001 for increase from baseline).

Conclusion: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.
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http://dx.doi.org/10.1097/QAD.0000000000001778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920693PMC
May 2018

Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial.

Lancet HIV 2018 04 16;5(4):e172-e180. Epub 2018 Jan 16.

School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Background: Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per μL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment.

Methods: The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per μL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per μL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048.

Findings: Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher.

Interpretation: Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per μL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment.

Funding: US National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(18)30003-1DOI Listing
April 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

Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia.

N Engl J Med 2017 10;377(15):1438-1447

From the Liberian Ministry of Health, Monrovia, Liberia (S.B.K., F.B., M.K., M.B., M.J., F.K., T.N.); the University of Minnesota, Division of Biostatistics, Minneapolis (G.G., B.G., J.W., J.D.N.); GlaxoSmithKline, Rockville (R.B.), and National Institutes of Health (R.E., D.F., L.H., E.H., M.N., H.C.L.) and AbViro (E.S.), Bethesda - all in Maryland; Merck, Kenilworth, NJ (M.F., S.G.); Battelle Memorial Institute, Columbus, OH (K.J., J.L., J.M., E.S.); International AIDS Vaccine Initiative, New York (M.F., S.G., T.M.); and GlaxoSmithKline, Rixensart, Belgium (F.R.).

Background: The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia.

Methods: We initiated a randomized, placebo-controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus vaccine (rVSV∆G-ZEBOV-GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated.

Results: A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSV∆G-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSV∆G-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSV∆G-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons).

Conclusions: A randomized, placebo-controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407 .).
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http://dx.doi.org/10.1056/NEJMoa1614067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705229PMC
October 2017

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial.

J Bone Miner Res 2017 Sep 26;32(9):1945-1955. Epub 2017 Jun 26.

St Vincent's Hospital, Sydney, Australia.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual-energy X-ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent-to-treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow-up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non-white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow-up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow-up, immediate ART resulted in greater BMD declines than deferred ART at the hip (-2.5% versus -1.0%; difference -1.5%, 95% confidence interval [CI] -2.2 to -0.8, p < 0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV-related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer-term consequences of the observed reductions in BMD is needed.

Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555813PMC
September 2017

Improved quality of life with immediate versus deferred initiation of antiretroviral therapy in early asymptomatic HIV infection.

AIDS 2017 04;31(7):953-963

aUniversity of Minnesota, Minneapolis, Minnesota bDenver Public Health, Denver, Colorado, USA cDesmond Tutu HIV Foundation, Cape Town, South Africa dKirby Institute, University of New South Wales, Sydney, Australia eRoyal Berkshire Hospital, Reading, Berkshire, UK fCentre Universitaire de Recherche Clinique, Bamako, Mali gInstitute of Tropical Medicine, Antwerp, Belgium hHospital Universitario de la Princessa, Madrid, Spain.

Objective: To determine if immediate compared to deferred initiation of antiretroviral therapy (ART) in healthy persons living with HIV had a more favorable impact on health-related quality of life (QOL), or self-assessed physical, mental, and overall health status.

Design: QOL was measured in the Strategic Timing of Antiretroviral Therapy study, which randomized healthy ART-naive persons living with HIV with CD4 cell counts above 500 cells/μl from 35 countries to immediate versus deferred ART.

Methods: At baseline, months 4 and 12, then annually, participants completed a visual analog scale (VAS) for 'perceived current health' and the Short-Form 12-Item Health Survey version 2 from which the following were computed: general health perception; physical component summary (PCS); and mental component summary (MCS); the VAS and general health were rated from 0 (lowest) to 100 (highest).

Results: QOL at study entry was high (mean scores: VAS = 80.9, general health = 72.5, PCS = 53.7, MCS = 48.2). Over a mean follow-up of 3 years, changes in all QOL measures favored the immediate group (P < 0.001); estimated differences were as follows: VAS = 1.9, general health = 3.6, PCS = 0.8, MCS = 0.9. When QOL changes were assessed across various demographic and clinical subgroups, treatment differences continued to favor the immediate group. QOL was poorer in those experiencing primary outcomes; however, when excluding those with primary events, results remained favorable for immediate ART recipients.

Conclusion: In an international randomized trial in ART-naive participants with above 500 CD4 cells/μl, there were modest but significant improvements in self-assessed QOL among those initiating ART immediately compared to deferring treatment, supporting patient-perceived health benefits of initiating ART as soon as possible after an HIV diagnosis.
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http://dx.doi.org/10.1097/QAD.0000000000001417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373969PMC
April 2017

Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy.

PLoS One 2016 12;11(5):e0155100. Epub 2016 May 12.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.

Background: Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.

Methods: In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower "usual" levels of IL-6 and D-dimer.

Results: Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower "usual" IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.

Conclusions: Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155100PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865234PMC
July 2017

Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection.

J Infect Dis 2016 Aug 30;214(3):408-16. Epub 2016 Apr 30.

Centre for Health and Infectious Diseases Research (CHIP), Department of Infectious Diseases, Rigshospitalet-University of Copenhagen, Denmark.

Background: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels are linked to adverse outcomes in human immunodeficiency virus (HIV) infection, but the strength of their associations with different clinical end points warrants investigation.

Methods: Participants receiving standard of care in 2 HIV trials with measured biomarker levels were followed to ascertain all-cause death, non-AIDS-related death, AIDS, cardiovascular disease (CVD), and non-AIDS-defining malignancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) of each end point for quartiles and log2-transformed IL-6, hsCRP, and D-dimer levels were calculated using Cox models. Marginal models modelling multiple events tested for equal effects of biomarker levels on different end points.

Results: Among 4304 participants, there were 157 all-cause deaths, 117 non-AIDS-related deaths, 101 AIDS cases, 121 CVD cases, and 99 non-AIDS-defining malignancies. IL-6 was more strongly associated with most end points, compared with hsCRP. IL-6 appeared to be a stronger predictor than D-dimer for CVD and non-AIDS-defining malignancies, but 95% CIs overlapped. Independent associations of IL-6 were stronger for non-AIDS-related death (HR, 1.71; 95% CI, 1.43-2.04) and all-cause death (HR, 1.56; 95% CI, 1.33-1.84) and similar for CVD (HR, 1.35; 95% CI, 1.12-1.62) and non-AIDS-defining malignancies (HR, 1.30; 95% CI, 1.06-1.61). There was heterogeneity of IL-6 (P < .001) but not hsCRP (P = .15) or D-dimer (P = .20) as a predictor for different end points.

Conclusions: IL-6 is a stronger predictor of fatal events than of CVD and non-AIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals.
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http://dx.doi.org/10.1093/infdis/jiw173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936649PMC
August 2016

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.

N Engl J Med 2015 Aug 20;373(9):795-807. Epub 2015 Jul 20.

Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.

Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).
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http://dx.doi.org/10.1056/NEJMoa1506816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569751PMC
August 2015

Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect.

J Neurovirol 2013 Aug 14;19(4):383-92. Epub 2013 Aug 14.

Coordinating Center for Biometric Research, University of Minnesota, Minneapolis, MN 55414, USA.

We evaluated factors associated with improvement in neurocognitive performance in 258 HIV-infected adults with baseline CD4 lymphocyte counts above 350 cells/mm³ randomized to intermittent, CD4-guided antiretroviral therapy (ART) (128 participants) versus continuous therapy (130) in the Neurology substudy of the Strategies for Management of Antiretroviral Therapy trial. Participants were enrolled in Australia, North America, Brazil, and Thailand, and neurocognitive performance was assessed by a five-test battery at baseline and month 6. The primary outcome was change in the quantitative neurocognitive performance z score (QNPZ-5), the average of the z scores of the five tests. Associations of the 6-month change in test scores with ART use, CD4 cell counts, HIV RNA levels, and other factors were determined using multiple regression models. At baseline, median age was 40 years, median CD4 cell count was 513 cells/mm³, 88 % had plasma HIV RNA ≤ 400 copies/mL, and mean QNPZ-5 was -0.68. Neurocognitive performance improved in both treatment groups by 6 months; QNPZ-5 scores increased by 0.20 and 0.13 in the intermittent and continuous ART groups, respectively (both P < 0.001 for increase and P = 0.26 for difference). ART was used on average for 3.6 and 5.9 out of the 6 months in the intermittent and continuous ART groups, respectively, but the increase in neurocognitive test scores could not be explained by ART use, changes in CD4, or plasma HIV RNA, which suggests a practice effect. The impact of a practice effect after 6 months emphasizes the need for a control group in HIV studies that measure intervention effects using neurocognitive tests similar to ours.
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http://dx.doi.org/10.1007/s13365-013-0190-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963803PMC
August 2013

Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART body composition substudy.

J Bone Miner Res 2013 Jun;28(6):1264-74

The Alfred Hospital and Monash University, Melbourne, Australia.

Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomized to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline and months 4 and 12; BMD at the spine (dual-energy X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared with the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p ≤ 0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, whereas increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.
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http://dx.doi.org/10.1002/jbmr.1861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657331PMC
June 2013

Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study.

Clin Trials 2013 30;10(1 Suppl):S5-S36. Epub 2012 Apr 30.

MRC Clinical Trials Unit, London, UK.

Background: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals.

Purpose: In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed.

Methods: A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naïve with CD4 count > 500 cells/µL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/µL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year.

Results: Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants.

Conclusions: START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials.
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http://dx.doi.org/10.1177/1740774512440342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664112PMC
January 2014

Considerations for Endpoint Selection When Designing HIV Clinical Trials.

Curr Infect Dis Rep 2012 Feb;14(1):110-8

Division of Biostatistics, University of Minnesota, 2221 University Ave SE, Suite 200, Minneapolis, MN, 55414, USA,

Selecting the primary endpoint is one of the most important decisions in designing clinical trials. Many HIV trials are powered for surrogate markers, often virologic suppression. Among 49 recently published Phase 3 or higher randomized HIV trials only 14% were powered for clinical outcomes such as the progression to AIDS, death, or serious non-AIDS diseases. We provide two examples where interventions modified the targeted surrogate markers but failed to provide clinical benefit. We review the use of surrogate and clinical endpoints, discuss the composition of clinical endpoints, and the need for endpoint verification. In HIV-infected individuals with CD4 cell counts above 200 cells/mm(3) serious non-AIDS conditions such as cardiovascular, renal, hepatic diseases and cancer contribute substantially to morbidity and mortality. In this population clinical endpoint trials should be powered for non-AIDS morbidity along with AIDS.
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http://dx.doi.org/10.1007/s11908-011-0231-7DOI Listing
February 2012

Analysis of biomarker data: logs, odds ratios, and receiver operating characteristic curves.

Curr Opin HIV AIDS 2010 Nov;5(6):473-9

School of Statistics, University of Minnesota, Minneapolis, MN 55455, USA.

Purpose Of Review: We discuss two data analysis issues for studies that use binary clinical outcomes (whether or not an event occurred): the choice of an appropriate scale and transformation when biomarkers are evaluated as explanatory factors in logistic regression and assessing the ability of biomarkers to improve prediction accuracy for event risk.

Recent Findings: Biomarkers with skewed distributions should be transformed before they are included as continuous covariates in logistic regression models. The utility of new biomarkers may be assessed by measuring the improvement in predicting event risk after adding the biomarkers to an existing model. The area under the receiver operating characteristic (ROC) curve (C-statistic) is often cited; it was developed for a different purpose, however, and may not address the clinically relevant questions. Measures of risk reclassification and risk prediction accuracy may be more appropriate.

Summary: The appropriate analysis of biomarkers depends on the research question. Odds ratios obtained from logistic regression describe associations of biomarkers with clinical events; failure to accurately transform the markers, however, may result in misleading estimates. Although the C-statistic is often used to assess the ability of new biomarkers to improve the prediction of event risk, other measures may be more suitable.
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http://dx.doi.org/10.1097/COH.0b013e32833ed742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157029PMC
November 2010

The effects of intermittent, CD4-guided antiretroviral therapy on body composition and metabolic parameters.

AIDS 2010 Jan;24(3):353-63

Infectious Diseases Unit, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, C/Villarroel 170, 08036 Barcelona, Spain.

Objective: To assess the effects of decreased antiretroviral therapy exposure on body fat and metabolic parameters.

Design: Substudy of the Strategies for Management of Anti-Retroviral Therapy study, in which participants were randomized to intermittent CD4-guided [Drug Conservation (DC) group] or to continuous [Viral Suppression (VS) group] antiretroviral therapy.

Methods: Participants at 33 sites were coenrolled in the Strategies for Management of Anti-Retroviral Therapy Body Composition substudy. Regional fat was assessed annually by whole-body dual-energy X-ray absorptiometry and abdominal computed tomography. Fasting metabolic parameters were assessed at months 4, 8, and annually. Treatment groups were compared for changes in fat and metabolic markers using longitudinal mixed models.

Results: Two hundred and seventy-five patients were randomized to the DC (n = 142) or VS (n = 133) group and followed for a median of 2.0 years. By month 12, limb fat (DC-VS difference 9.8%, 95% confidence interval 3.5-16.1; P = 0.003) and subcutaneous abdominal fat (DC-VS difference 14.3 cm, 95% confidence interval -0.1 to 28.7; P = 0.05) increased in the DC group. There was no treatment difference in visceral abdominal fat (DC-VS difference -2.1%, 95% confidence interval -13.5 to 9.4; P = 0.72). Lipids significantly decreased in the DC group by month 4 and treatment differences persisted throughout follow-up (P < or = 0.001). By 12 months, hemoglobin A1C increased in the DC (+0.3%) and remained stable in the VS group (P = 0.003); the treatment difference remained significant throughout follow-up (P = 0.02).

Conclusion: After 12 months, intermittent antiretroviral therapy increased subcutaneous fat, had no effect on visceral abdominal fat, decreased plasma lipids, and increased hemoglobin A1C compared with continuous antiretroviral therapy.
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http://dx.doi.org/10.1097/QAD.0b013e3283333666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902280PMC
January 2010

Continuous antiretroviral therapy decreases bone mineral density.

AIDS 2009 Jul;23(12):1519-29

Coordinating Center for Biometric Research, University of Minnesota, Minneapolis, Minnesota 55414, USA.

Objectives: To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) DESIGN: Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) SETTING: Outpatient clinics in the United States, Australia, and Spain.

Participants: Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy.

Main Outcome Measures: Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT).

Methods: Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated.

Results: The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores -0.5 total hip, -0.7 spine DXA, -0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6-2.3; P = 0.002], 1.3% (spine DXA; 95% CI 0.1-2.4, P = 0.03), and 3.0% (spine qCT; 95% CI 0.8-5.2, P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1-22.5; P = 0.04).

Conclusion: Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.
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http://dx.doi.org/10.1097/QAD.0b013e32832c1792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748675PMC
July 2009

Earlier initiation of antiretroviral therapy in treatment-naïve patients: implications of results of treatment interruption trials.

Curr Opin HIV AIDS 2008 Mar;3(2):112-7

aDivision of Biostatistics, School of Public Health, USA bSchool of Statistics, University of Minnesota, Minneapolis, Minnesota, USA.

Purpose Of Review: To discuss the implications of the results of the Strategies for Management of Antiretroviral Therapy Study and other treatment interruption studies on the question of when antiretroviral therapy should be initiated.

Recent Findings: In the Strategies for Management of Antiretroviral Therapy Study, CD4 count-guided, episodic use of antiretroviral therapy as compared with continuous antiretroviral therapy resulted in an increased risk of all-cause mortality, almost entirely due to causes other than AIDS, and a composite outcome of cardiovascular disease, renal disease and liver disease. Subgroup analyses in the Strategies for Management of Antiretroviral Therapy Study indicated that the increased risk in the episodic antiretroviral therapy group compared with the continuous antiretroviral therapy group was evident in patients taking antiretroviral therapy at entry (antiretroviral therapy stopped after randomization) and in patients not taking antiretroviral therapy at entry (patients remained off antiretroviral therapy until their CD4 count declined to below 250 cells/mm).

Summary: The Strategies for Management of Antiretroviral Therapy Study did not directly address the 'when to start' question. Data from the Strategies for Management of Antiretroviral Therapy Study and other studies strongly suggest, however, that the use of antiretroviral therapy earlier than recommended by current guidelines warrants investigation. Definitive data from randomized studies that are powered to reliably assess risks and benefits are needed to guide when antiretroviral therapy is initiated.
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March 2008
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