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Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%–36%) in Black, 60% (CI, 32%–84%) in White, and 29% (CI, 8%–58%) in Hispanic participants; negative predictive values were 97% (CI, 93%–99%), 95% (CI, 90%–98%), and 97% (CI, 90%–100%), respectively. Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.

Background: Successful hepatitis C virus (HCV) treatment may reduce cardiovascular disease (CVD) risk and improve levels of CVD biomarkers produced outside the liver (nonhepatic biomarkers). Methods: Stored serum or plasma from before and 24 weeks after end of HCV treatment (EOT) from human immunodeficiency virus (HIV)/HCV-coinfected subjects who received up to 72 weeks of peginterferon/ribavirin, 27 with and 27 without sustained virologic response (SVR) matched by race, ethnicity and sex, were tested for nonhepatic (soluble intercellular adhesion molecule-1 [sICAM-1], soluble P-selectin [sP-selectin], interleukin [IL]-6, d-dimer, and lipoprotein-associated phospholipase A2 [Lp-PLA2]) and hepatic (cholesterol and high-sensitivity C-reactive protein) CVD and macrophage activation markers (soluble CD163 [sCD163] and soluble CD14). Changes in biomarkers and their association with SVR were examined by t tests or Wilcoxon tests and regression models. Results: Of the 54 subjects, 30 were white, 24 were black, and 44 were male. Pretreatment levels of nonhepatic biomarkers were high: sICAM-1 overall median, 439.2 ng/mL (interquartile range [IQR], 365.6–592.8]; sP-selectin, 146.7 ng/mL (IQR, 94.1–209.9), and IL-6, 2.32 pg/mL (IQR, 1.61–3.49). Thirty-seven of 52 (71%) subjects had Lp-PLA2 >235 ng/mL. Sustained virologic response was associated with decrease in sICAM-1 (P = .033) and sCD163 (P = .042); this result was attenuated after controlling for changes in the alanine aminotransferase level. At 24 weeks after EOT, 17 (63%) SVRs had Lp-PLA2 >235 ng/mL vs 25 (93%) non-SVRs (P = .021). Conclusions: Hepatitis C virus clearance may reduce hepatic and, subsequently, systemic inflammation and CVD risk in HIV/HCV coinfection.

Background: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs., Methods: Participants were nonhospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S-gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant., Results: Study participants receiving single- or dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared with single-active mAb treatment, treatment with dual-active mAbs led to faster viral load decline at study days 3 (P < .001) and 7 (P < .01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than with placebo (2.6% vs 0%; P < .001) and were more frequently detected in the setting of single-active compared with dual-active mAb treatment (7.3% vs 1.1%; P < .01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death., Conclusions: Compared with single-active mAb therapy, dual-active mAbs led to similar clinical outcomes but significantly faster viral load decline and a lower risk of emergent resistance., Competing Interests: Potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Therapeutic monoclonal antibodies (mAbs) have been studied in humans, but the impact on immune memory of mAb treatment during an ongoing infection has remained unclear. We evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific reduction in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating memory B cell responses to infection, and single mAb administration can continue to impact memory B cell responses to additional antigen exposures months later., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: To address the need for novel COVID-19 therapies, we evaluated the fully-human polyclonal antibody product SAB-185 in a phase 3 clinical trial., Methods: Non-hospitalized high-risk adults within 7 days of COVID-19 symptom onset were randomized 1:1 to open-label SAB-185 3,840 units/kg or casirivimab/imdevimab 1200 mg. Non-inferiority comparison was undertaken for the pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active). Primary outcomes were the composite of all-cause hospitalizations/deaths and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. Secondary outcomes included time to sustained symptom improvement and resolution., Results: Enrollment was terminated early due to low hospitalization/death rates upon Omicron emergence. 733 adults were randomized, 255 included in pre-Omicron and 392 in Omicron analysis populations. Hospitalizations/deaths occurred in 6 (5.0%) and 3 (2.2%) of pre-Omicron SAB-185 and casirivimab/imdevimab arms, respectively (absolute difference [95% CI] 2.7% [-2.3%, 8.6%]), inconclusive for non-inferiority; and 5 (2.5%) versus 3 (1.5%) (absolute difference 1.0% [-2.3%, 4.5%]) for Omicron. Risk ratios for grade ≥3 TEAEs were 0.94 [0.52, 1.71] (pre-Omicron) and 1.71 [0.96, 3.07] (Omicron). Time to symptom improvement and resolution were shorter for SAB-185, median 11 vs 14 (pre-Omicron) and 11 vs 13 days (Omicron) (symptom improvement), and 16 vs 24 days and 18 vs >25 days (symptom resolution), p<0.05 for symptom resolution for Omicron only., Conclusions: SAB-185 had an acceptable safety profile with faster symptom resolution in the Omicron population. Additional studies are needed to characterize its efficacy for COVID-19., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Reliable biomarkers of coronavirus disease 2019 (COVID-19) outcomes are critically needed. We evaluated associations of spike antibody (Ab) and plasma nucleocapsid antigen (N Ag) with clinical outcomes in nonhospitalized persons with mild-to-moderate COVID-19., Methods: Participants were nonhospitalized adults with mild-to-moderate COVID-19 enrolled in ACTIV-2 between January and July 2021 and randomized to placebo. We used quantitative assays for severe acute respiratory syndrome coronavirus 2 spike Ab and N Ag in blood and determined numbers of hospitalization/death events within 28 days and time to symptom improvement., Results: Of 209 participants, 77 (37%) had quantifiable spike Ab and 139 (67%) quantifiable N Ag. Median age was 50 years; 111 (53%) were female, 182 (87%) White, and 105 (50%) Hispanic/Latino. Higher risk of hospitalization/death was seen with unquantifiable (22/132 [16.7%]) versus quantifiable (1/77 [1.3%]) spike Ab (risk ratio [RR], 12.83 [95% confidence interval {CI}, 1.76-93.34]) and quantifiable (22/139 [15.8%]) vs unquantifiable (1/70 [1.4%]) N Ag (RR, 11.08 [95% CI, 1.52-80.51]). Increasing risk of hospitalizations/deaths was seen with increasing N Ag levels. Time to symptom improvement was longer with unquantifiable versus quantifiable spike Ab (median, 14 [interquartile range {IQR}, 8 to >27] vs 8 [IQR, 4-22] days; adjusted hazard ratio [aHR], 0.66 [95% CI, .45-.96]) and with quantifiable versus unquantifiable N Ag (median, 12 [7 to >27] vs 10 [5-22] days; aHR, 0.79 [95% CI, .52-1.21])., Conclusions: Absence of spike Ab and presence of plasma N Ag predicted hospitalization/death and delayed symptom improvement in COVID-19 outpatients., Competing Interests: Potential conflicts of interest. N. J. received salary support to the institution from Sagent Pharmaceuticals. D. A. W. has received funding to his institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. T. H. E. serves as a consultant for Tonix Pharmaceuticals. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through his institution from Gilead Sciences and GSK/ViiV. J. Z. L. has received research funding from Merck. J. J. E. is an ad hoc consultant to GSK/VIR, data monitoring committee chair for Adagio Phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. K. W. C. received research funding to the institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: We evaluated associations between antepartum weight change and adverse pregnancy outcomes and between antiretroviral therapy (ART) regimens and week 50 postpartum body mass index in IMPAACT 2010., Methods: Women with human immunodeficiency virus (HIV)-1 in 9 countries were randomized 1:1:1 at 14-28 weeks' gestational age (GA) to start dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) versus DTG + FTC/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/FTC/TDF. Insufficient antepartum weight gain was defined using Institute of Medicine guidelines. Cox-proportional hazards regression models were used to evaluate the association between antepartum weight change and adverse pregnancy outcomes: stillbirth (≥20 weeks' GA), preterm delivery (<37 weeks' GA), small size for GA (<10th percentile), and a composite of these endpoints., Results: A total of 643 participants were randomized: 217 to the DTG + FTC/TAF, 215 to the DTG + FTC/TDF, and 211 to the EFV/FTC/TDF arm. Baseline medians were as follows: GA, 21.9 weeks; HIV RNA, 903 copies/mL; and CD4 cell count, 466/μL. Insufficient weight gain was least frequent with DTG + FTC/TAF (15.0%) versus DTG + FTC/TDF (23.6%) and EFV/FTC/TDF (30.4%). Women in the DTG + FTC/TAF arm had the lowest rate of composite adverse pregnancy outcome. Low antepartum weight gain was associated with higher hazard of composite adverse pregnancy outcome (hazard ratio, 1.44 [95% confidence interval, 1.04-2.00]) and small size for GA (1.48 [.99-2.22]). More women in the DTG + FTC/TAF arm had a body mass index ≥25 (calculated as weight in kilograms divided by height in meters squared) at 50 weeks postpartum (54.7%) versus the DTG + FTC/TDF (45.2%) and EFV/FTC/TDF (34.2%) arms., Conclusions: Antepartum weight gain on DTG regimens was protective against adverse pregnancy outcomes typically associated with insufficient weight gain, supportive of guidelines recommending DTG-based ART for women starting ART during pregnancy. Interventions to mitigate postpartum weight gain are needed., Competing Interests: Potential conflicts of interest. R. M. H. is an Elsevier ClinicalKey editorial board member. R. M. H. also reports honoraria for lectures on this topic from the Los Angeles County Division of HIV and STI Programs and the UCLA CARE Center’s continuing medical education seminars. S. B. and L. Z. reports support for the present work from the NIH Division of AIDS/Eunice Kennedy Shriver National Institute of Child Health and Human Development and ViiV/GSK, paid to their institution. L. F. reports grants or contracts for the current study through NIH/IMPAACT. S. H. reports grants or contracts from UKZN Developing Research Innovation, Localisation and Leadership in South Africa (DRILL), the Fogarty International Center, the NIH Common Fund, Office of Strategic Coordination, Office of the Director, Office of AIDS Research, the NIH Office of the Director, the National Institute of Mental Health, NIH (award D43TW010131, paid to their institution, from January 2018 to July 2023), and the SA National Research Foundation (Thuthuka funding grant, paid to their institution, from January 2019 to December 2021). R. Z. reports receipt of study medication from ViiV healthcare for a federally funded research study (as principal investigator); ViiV is donating long-acting cabotegravir for an implementation study of preexposure prophylaxis in Botswana, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. J. S. C. is a scientific advisor for Merck, participating on its advisory board, and reports royalties or licenses from UpToDate. P. S. reports grants or contracts from Gilead and ViiV; consulting fees from Gilead, Janssen, Merck, and ViiV; and participation on a data safety monitoring board or advisory board for Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population., Methods: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates., Results: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001)., Conclusions: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH., Competing Interests: Potential conflicts of interest. B. F. reports institutional research support from AstraZeneca, MedImmune, and MedTrace, all outside of the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc., relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI (RO1AI123001 PI, R01 HL137562 PI, R01HL146267 PI, K24AI157882 PI, U01HL123336 Co-I, U01HL123336-06S2 Co-I, R01HL151283 Co-I) outside the submitted work; travel support from conference organizing committees for CROI and International Workshop for HIV and Women; and unpaid participation in DSMB for NIH-funded studies. A. L. reports institutional research support from NIH/NIA, outside of the submitted work. T. H. B. reports equity in Excision Bio Therapeutics and serves on its Scientific Advisory Board, outside the submitted work. G. S. B. reports research grants (R01HL157531, U01HL146382, R56HL152803, R01MD013493) and royalties from UpToDate.com. C. D. M. reports institutional research support by Lilly and personal fees from ViiV Healthcare, Pfizer, and Gilead Sciences for participation in advisory board meetings outside the submitted work. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for data safety monitoring or advisory boards from Kintor Pharmaceuticals, Glaxo Smith Kline, and Merck; all outside the submitted work. J. S. C. reports consulting fees from Merck and Company. H. J. R. reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study as well as grants from NIH/NIAID, and NIH/NHLBI, NIH/NIDDK, and NIH/NIA outside the submitted work. U. H. reports institutional research support from Kowa, AstraZeneca, MedImmune, and HeartFlow; consulting fees from Recor Medical, Stanford University, Clinical Cardiovascular Sciences, MedTrace Inc., and Rapid AI; stock or stock options in Cleerly Inc. as Chief Scientific Officer; and personal fees from Duke University, all outside of the submitted work. M. T. L. reports grant support through his institution from NIH/NHLIBI and Kowa Pharmaceuticals America, Inc., for the conduct of the study; institutional grant support from MedImmune, CRICO, Ionis, Johnson & Johnson Innovation, National Academy of Medicine, and Astrazeneca; and personal fees from PQBypass, outside of the current work. P. S. D. reports consulting fees from Foresite Labs; receipt of equipment or drugs from Kowa and Caption Health; and an institutional grant for HeartFlow (outside of the current work). S. K. G. reports grants from NIH, KOWA Pharmaceuticals, Gilead Sciences, and ViiV Healthcare during the conduct of the study as well as personal consulting fees from TheraTechnologies, Navidea, and ViiV Healthcare, and Marathon Asset Management outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults., Methods: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28., Results: Of 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. C. B. M. participated on a data safety monitoring board for the BONE STAR study. K. W. C. has received research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. J. S. C. has consulted for Merck and Company. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly imputed values can lead to biased estimates of treatment effects. In this article, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values

Background: Prospective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401., Methods: Data were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models., Results: Among 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34- 4.32]), female sex (aRR, 1.91 [95% CI, 1.28-2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19-3.13]), and presence of symptoms 22-28 days posttreatment (aRR, 2.70 [95% CI, 1.63-4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not., Conclusions: Long COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22-28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention., Clinical Trials Registration: NCT04518410., Competing Interests: Potential conflicts of interest. T. H. E. serves as a consultant for Tonix Pharmaceuticals. N. J. received salary support to the institution from Sagent Pharmaceuticals. D. A. W. has received funding to his institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through his institution from Gilead Sciences and GSK/ViiV. J. Z. L. has received research funding from Merck. P. K. is an employee and shareholder of Eli Lilly. J.J.E. is an ad hoc consultant to GSK/VIR, data monitoring committee chair for Adagio Phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. K. W. C. received research funding to institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410., Competing Interests: Potential conflicts of interest. JSC has consulted for Merck and Company. KWC reports research funding to the institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. CM participated on a Data Safety Monitoring Board for the BONE STAR study. JJE is an ad hoc consultant to GSK/VIR and data monitoring committee chair for Adagio Phase III studies. DMS has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. DAW has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. ESD receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through the institution from Gilead Sciences and GSK/ViiV. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation., Methods: ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo., Results: The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences., Conclusions: There was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms., Clinical Trials Registration: NCT04518410., Competing Interests: Potential conflicts of interest . K. W. C. reports research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. D. A. W. has received funding to the institution to support research; and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19)., Methods: Anterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death., Results: One hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04-1.49]) among placebo recipients, ranging from 3% to 16% for <2 to ≥6 log10 copies/mL. Although only 1% had quantifiable levels, there was a similar trend across day 0 plasma RNA categories. Higher day 3 AN RNA was associated with subsequent hospitalization/death among placebo recipients (RR, 1.42 per log10 copies/mL [95% CI, 1.00-2.03]), but not mAb recipients (RR, 1.02 per log10 copies/mL [95% CI, 0.68-1.56]). The proportion of treatment effect (reduction in hospitalizations/deaths after day 3 for mAb vs placebo) explained by day 3 AN RNA was 8%., Conclusions: SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting, but AN RNA levels may not be a reliable surrogate marker of mAb treatment effect in COVID-19 trials. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. has received research funding (paid to institution) from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. J. J. E. is an ad hoc consultant to GSK/VIR and the data monitoring committee chair for Adagio phase 3 studies. J. Z. L. has consulted for AbbVie. W. A. F. has received research funding (paid to institution) from Ridgeback Biopharmaceuticals; served on adjudication committees for Janssen and Syneos; and consulted for Roche and Merck. P. K. is an employee and shareholder of Eli Lilly. D. M. is an employee of Brii Biosciences. D. A. W. has received funding (paid to institution) to support research and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. has received consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support (paid to institution) from GSK and ViiV. J. S. C. has consulted for Merck and Co. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. receives research funding from Merck, Sharp & Dohme (paid to institution) and Amgen (research contract with institution); consultancy for Pardes Biosciences; honoraria to the author for continuing medical education presentations (not-for-profit organization) from the International Antiviral Society–USA (IAS-USA); and participation on a data and safety monitoring board (DSMB) or advisory board for the University of California, San Francisco (UCSF) (served as Chair of a safety monitoring committee for an investigator-initiated study where the sponsor is UCSF). E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; research support through the institution from Gilead Sciences and GSK/ViiV; participation on a DSMB or advisory board for Gilead and ViiV; and reports support from NIH. D. A. W. has received funding to institution to support research and honoraria for advisory boards and consulting from Gilead Sciences and grant or contracts from Lilly. J. Z. L. has consulted for AbbVie and received a research grant from Merck. J. J. E. is an ad hoc consultant to GSK/Vir Biotechnology and is data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Co and reports a leadership or fiduciary role in other board, society, committee, or advocacy groups as a volunteer for the Board of Directors of the IAS-USA and the Foundation Board, Conference on Retroviruses and Opportunistic Infections. D. M. S. has consulted for Bayer Healthcare, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, and Pharma Holdings; has grants or contracts from NIH (DK131532, AI169609, DA047039, AI036214, AI131385, AI100665, AI126620, funding provided to institution), the James B. Pendleton Charitable Trust John, and the Mary Tu Foundation, including payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events for Medscape (COVID treatment), American Institute continuing medical education (COVID treatment), and Kiadis; stock or stock options for Model Medicine, Linear Therapies, and Cv Biosciences; and receipt of equipment, materials, drugs, medical writings, gifts, or other services from the James B. Pendleton Charitable Trust. C. M. reports participation on a DSMB for BONE STAR. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. received research funding to institution from Merck Sharp & Dohme, and was a consultant for Pardes Biosciences. J. Z. L. was a consultant for AbbVie and received research support from Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: SAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19)., Methods: Participants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28., Results: Two-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo., Conclusions: SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. B. T. has received honoraria for advisory boards and consulting from Gilead Sciences. K. W. C. has received research funding to the institution from Merck Sharp & Dohme and consulted for Pardes Biosciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. J. Z. L. has consulted for Abbvie. A. L. G. reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic; and research support from Gilead and Merck, outside of the described work. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. C. B. and T. L. are employees of SAB Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein., Methods: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score., Results: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055)., Conclusions: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015)., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH., Methods: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL)., Results: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels., Conclusions: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects., Clinical Trials Registration: NCT0234429., Competing Interests: Potential conflicts of interest. S. E. L. reports travel reimbursement from the Association of Nurses in AIDS Care as an invited presenter and receipt of a 1-time conference travel reimbursement. A. K. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study. T. H. B. reports equity in Excision Bio Therapeutics and serves on their scientific advisory board outside the submitted work. J. S. C. reports consulting fees from Merck and Company and Resvirlogix. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Janssen, AbbVie, Merck, Amgen, and Cytodyn outside the submitted work and serves as chair of the data and safety monitoring board (DSMB) for the Intrepid Study. E. T. O. reports grant support through his institution from NIH, Gilead Sciences, ViiV, and GlaxoSmithKline and personal fees from Merck, ViiV Healthcare, and Theratechnologies outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from GlaxoSmithKline/ViiV Healthcare and Merck, all outside the submitted work. C. D. M. reports personal fees from Gilead Sciences and ViiV Healthcare for participation in advisory board meetings outside the submitted work. K. M. E. reports grant support from Gilead Sciences and consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen Therapeutics (all paid to the University of Colorado) outside the submitted work. M. C. reports serving as an executive board member for HIV Medicine Association and participation on boards for ViiV Healthcare and Gilead Sciences. M. M. reports personal fees from Merck and Company, Gilead Sciences, and ViiV outside the submitted work. M. T. L. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study and reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass outside the current work. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies Consulting, Navidea, and ViiV Healthcare Consulting, all outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging outside the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI outside the submitted work; support for the Conference on Retroviruses and Opportunistic Infections and International Workshop for HIV and Women from the conference organizing committee as an abstract reviewer and/or speaker; and participation in DSMB for NIH-funded studies and received no payment., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Little is known regarding coronavirus disease 2019 (COVID-19) vaccination rates in people with HIV (PWH), a vulnerable population with significant morbidity from COVID-19. We assessed COVID-19 vaccination rates among 6952 PWH in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) compared to region- and country-specific vaccination data. The global probability of COVID-19 vaccination through end of July 2021 was 55% among REPRIEVE participants with rates varying substantially by Global Burden of Disease (GBD) superregion. Among PWH, factors associated with COVID-19 vaccination included residence in high-income regions, age, white race, male sex, body mass index, and higher cardiovascular risk. Clinical Trials Registration. NCT02344290., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Context: Disentangling contributions of HIV from antiretroviral therapy (ART) and understanding the effects of different ART on metabolic complications in persons living with HIV (PLHIV) has been challenging., Objective: We assessed the effect of untreated HIV infection as well as different antiretroviral therapy (ART) on the metabolome/lipidome., Methods: Widely targeted plasma metabolomic and lipidomic profiling was performed on HIV-seronegative individuals and people living with HIV (PLHIV) before and after initiating ART (tenofovir/emtricitabine plus atazanavir/ritonavir [ATV/r] or darunavir/ritonavir [DRV/r] or raltegravir [RAL]). Orthogonal partial least squares discriminant analysis was used to assess metabolites/lipid subspecies that discriminated between groups. Graphical lasso estimated group-specific metabolite/lipid subspecies networks associated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Correlations between inflammatory markers and metabolites/lipid subspecies were visualized using heat maps., Results: Of 435 participants, 218 were PLHIV. Compared to HIV-seronegative individuals, ART-naive PLHIV exhibited higher levels of saturated triacylglycerols/triglycerides (TAGs) and 3-hydroxy-kynurenine, lower levels of unsaturated TAGs and N-acetyl-tryptophan, and a sparser and less heterogeneous network of metabolites/lipid subspecies associated with HOMA-IR. PLHIV on RAL vs ATV/r or DRV/r had lower saturated and unsaturated TAGs. Positive correlations were found between medium-long chain acylcarnitines (C14-C6 ACs), palmitate, and HOMA-IR for RAL but not ATV/r or DRV/r. Stronger correlations were seen for TAGs with interleukin 6 and high-sensitivity C-reactive protein after RAL vs ATV/r or DRV/r initiation; these correlations were absent in ART-naive PLHIV., Conclusion: Alterations in the metabolome/lipidome suggest increased lipogenesis for ART-naive PLHIV vs HIV-seronegative individuals, increased TAG turnover for RAL vs ATV/r or DRV/r, and increased inflammation associated with this altered metabolome/lipidome after initiating ART. Future studies are needed to understand cardiometabolic consequences of lipogenesis and inflammation in PLHIV., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens., Methods: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation., Results: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70])., Conclusions: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Adipose tissue (AT) alterations are common in people living with human immunodeficiency virus (PLWH). Decreases in AT density suggest disrupted adipocyte function/hypertrophy. We assessed changes in AT density after antiretroviral therapy (ART) initiation and associations with immunometabolic parameters., Methods: In a prospective randomized clinical trial of ART initiation, L4-L5 abdominal CT scans measured subcutaneous AT (SAT) and visceral AT (VAT) area and density in treatment-naive PLWH randomized to tenofovir-emtricitabine plus ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Linear regression models compared week 0 and week 96 levels, and 96-week changes, in SAT and VAT density (in Hounsfield units [HU]). Spearman correlations assessed relationships between AT density and immunometabolic parameters., Results: Of the 228 participants, 89% were male and 44% were white non-Hispanic. Median age was 36 years, baseline HIV-1 RNA was 4.6 log10 copies/mL, and CD4+ T-cell count was 344 cells/μL. Over 96 weeks, SAT and VAT HU decreased significantly in all arms. Less dense week 96 SAT and VAT density correlated with higher high-density lipoprotein (HDL) cholesterol and adiponectin (r = 0.19-0.30) levels and lower interleukin 6, non-HDL cholesterol, triglyceride, leptin, and homeostatic model assessment of insulin resistance (r = -0.23 to -0.68) levels at week 96 after adjusting for baseline CD4+ T-cell count, HIV-1 RNA, and baseline AT area., Conclusions: Following virologic suppression, lower SAT and VAT density was associated with greater plasma measures of systemic inflammation, lipid disturbances, and insulin resistance independent of AT area, suggesting that changes in AT density with ART may lead to adverse health outcomes independent of AT quantity., Clinical Trials Registration: NCT00851799., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described., Methods: The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics., Results: A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status., Conclusions: There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV., Clinical Trials Registration: NCT02344290., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial., Methods: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model., Results: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy., Conclusions: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed., Clinical Trials Registration: NCT0234429., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants., Methods: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content., Results: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively)., Conclusions: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group., Clinical Trials Registration: NCT02344290; NCT03238755., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

In a retrospective case control analysis, following adjustments for high-sensitivity C-reactive protein (hsCRP), traditional cardiovascular risk factors, and the CD4/CD8 T-cell ratio, higher lipopolysaccharide-binding protein (LBP) was associated with future myocardial infarctions in hsCRP human immunodeficiency virus (HIV). LBP may be a marker of cardiovascular risk with utility in HIV., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Chronic inflammation in treated HIV infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV., Methods: This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD)., Results: The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T cells at week 24 and CD8+ T cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo., Conclusions: Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation., Clinical Trials Registration: NCT01949116., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Fat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear., Methods: Human immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT)., Results: : 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks., Conclusions: While ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Concentrations of antiretrovirals in hair are associated with virologic outcomes in cohorts of human immunodeficiency virus (HIV)-positive individuals but have never been examined in a clinical trial. We show for the first time the predictive utility of hair antiretroviral concentrations in a large HIV treatment-naive trial (AIDS Clinical Trials Group protocol A5257)., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Adverse pregnancy outcomes for women who conceive on antiretroviral therapy (ART) may be increased, but data are conflicting., Methods: Human immunodeficiency virus-infected, nonbreastfeeding women with pre-ART CD4 counts ≥400 cells/μL who started ART during pregnancy were randomized after delivery to continue ART (CTART) or discontinue ART (DCART). Women randomized to DCART were recommended to restart if a subsequent pregnancy occurred or for clinical indications. Using both intent-to-treat and as-treated approaches, we performed Fisher exact tests to compare subsequent pregnancy outcomes by randomized arm., Results: Subsequent pregnancies occurred in 277 of 1652 (17%) women (CTART: 144/827; DCART: 133/825). A pregnancy outcome was recorded for 266 (96%) women with a median age of 27 years (interquartile range [IQR], 24-31 years) and median CD4+ T-cell count 638 cells/μL (IQR, 492-833 cells/μL). When spontaneous abortions and stillbirths were combined, there was a significant difference in events, with 33 of 140 (23.6%) in the CTART arm and 15 of 126 (11.9%) in the DCART arm (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.1-3.5]; P = .02). In the as-treated analysis, the RR was reduced and no longer statistically significant (RR, 1.4 [95% CI, .8-2.4])., Conclusions: Women randomized to continue ART who subsequently conceived were more likely to have spontaneous abortion or stillbirth, compared with women randomized to stop ART; however, the findings did not remain significant in the as-treated analysis. More data are needed on pregnancy outcomes among women conceiving on ART, particularly with newer regimens.

Background: Fibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection., Methods: In this 48-week, randomized, controlled trial, adults continued HIV-suppressive ART and received telmisartan or no drug. Collagen I, fibronectin, and phosphorylated SMAD3 (pSMAD3) deposition in lymph nodes, as well as collagen I, collagen VI, and fibronectin deposition in adipose tissue, were quantified by immunohistochemical analysis at weeks 0 and 48. Two-sided rank sum and signed rank tests compared changes over 48 weeks., Results: Forty-four participants enrolled; 35 had paired adipose tissue specimens, and 29 had paired lymph node specimens. The median change overall in the percentage of the area throughout which collagen I was deposited was -2.6 percentage points (P = 0.08) in lymph node specimens and -1.3 percentage points (P = .001) in adipose tissue specimens, with no between-arm differences. In lymph node specimens, pSMAD3 deposition changed by -0.5 percentage points overall (P = .04), with no between-arm differences. Telmisartan attenuated increases in fibronectin deposition (P = .06). In adipose tissue, changes in collagen VI deposition (-1.0 percentage point; P = .001) and fibronectin deposition (-2.4 percentage points; P < .001) were observed, with no between-arm differences., Conclusions: In adults with treated HIV infection, lymph node and adipose tissue fibrosis decreased with continued ART alone, with no additional fibrosis reduction with telmisartan therapy.

Background: Obesity and lipohypertrophy are common in treated human immunodeficiency virus (HIV) infection and contribute to morbidity and mortality among HIV-infected adults on antiretroviral therapy (ART)., Methods: We present a consensus opinion on the diagnosis, clinical consequences, and treatment of excess adiposity in adults with treated HIV infection., Results: Obesity and lipohypertrophy commonly occur among HIV-infected adults on ART and may have overlapping pathophysiologies and/or synergistic metabolic consequences. Traditional, HIV-specific, and ART-specific risk factors all contribute. The metabolic and inflammatory consequences of excess adiposity are critical drivers of non-AIDS events in this population. Although promising treatment strategies exist, further research is needed to better understand the pathophysiology and optimal treatment of obesity and lipohypertrophy in the modern ART era., Conclusions: Both generalized obesity and lipohypertrophy are prevalent among HIV-infected persons on ART. Aggressive diagnosis and management are key to the prevention and treatment of end-organ disease in this population and critical to the present and future health of HIV-infected persons., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

It is unclear whether differential roles of CD4(+) versus CD8(+) T-cell senescence/exhaustion and effects of antiretroviral therapy (ART) on these processes may contribute to morbidity in treated human immunodeficiency virus type 1 (HIV) infection. In a prospective 96-week trial, 328 HIV-infected ART-naive participants were randomly assigned to receive tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. Markers of CD4(+) T-cell senescence (ie, the percentage of CD28(-)CD57(+) cells among CD4(+) T cells ) and CD4(+)/CD8(+) T-cell exhaustion (ie, the percentage of PD-1(+) cells among CD4(+)/CD8(+) T cells) decreased after ART. There were no changes in markers of CD8(+) T-cell senescence after ART and no differential changes in all markers in ART groups. Senescent CD4(+) and CD8(+) T cells may have differential roles in HIV pathogenesis., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis., Methods: We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima-media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6-75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs., Results: We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV-infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age., Conclusions: The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Data on effectiveness of preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV)-uninfected women attempting conception with HIV-infected male partners are limited to observational studies., Methods: To explore the benefits of PrEP for conception, we developed a model to estimate the average annual probability of a woman remaining HIV-uninfected and having a child ("successful" outcome) via condomless sex with an HIV-infected male. The outcome likelihood is dependent upon parameters defining HIV-1 infectivity. We simulated 2 scenarios: optimal (condomless sex acts limited to the ovulation window), and suboptimal (acts not limited to ovulation)., Results: In the optimal scenario when the male is on antiretroviral therapy (ART), the average annual probability of the successful outcome is 29.1%, increasing to 29.2% with the addition of PrEP (P = .45). In the suboptimal scenario, the probability is 26.8% with ART alone versus 27.3% with ART/PrEP (P < .0001). Older maternal age reduces the probability of success in both scenarios, particularly after age 30., Conclusions: In our model, PrEP provides little added benefit when the HIV-infected male partner is on ART, condomless sex is limited to the ovulation window, and other modifiable transmission risks are optimized. Older female age decreases the probability of success by increasing the number of condomless sex acts required for conception., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation., Methods: We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss., Results: At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss., Conclusions: BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Low levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with increased cardiovascular disease (CVD) risk., Methods: Virologically controlled participants without CVD on stable ART with low HDL-C (men <40 mg/dL, women <50 mg/dL) and triglycerides >150 mg/dL were randomized to receive open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks. The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in participants with complete follow-up scans., Results: Of 99 participants, 74 had complete data (35 niacin, 39 fenofibrate). Median age was 45 years, 77% were male, median CD4(+) count was 561 cells/µL, and brachial FMD was 4.2%. Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the median (interquartile range) change was +0.6% (-1.6 to 2.3) with niacin (P = .28) and +0.5% (-1.0 to 3.0) with fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels., Conclusions: Despite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or inflammatory markers in participants with well-controlled HIV infection and low HDL-C., Clinical Trials Registration: NCT01426438., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: It is unclear whether the integrase inhibitor raltegravir (RAL) reduces inflammation and immune activation compared with ritonavir-boosted protease inhibitors (PIs)., Methods: In a prospective, randomized, multicenter clinical trial that included 328 human immunodeficiency type 1 (HIV-1)-infected, treatment-naive participants were randomized to receive tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or RAL. A total of 234 participants (71%) with HIV-1 RNA levels <50 copies/mL by week 24 were included. Plasma biomarkers of inflammation and coagulation that were analysed included high-sensitivity C-reactive protein, interleukin-6 (IL-6), GlycA, D-dimer, soluble CD14 (sCD14), sCD163, and sIL-2r; blood cellular markers included %CD38+DR+ of T-cell subsets and %CD14+CD16+ and%CD14(dim)CD16+ monocyte subsets. Changes from baseline were examined at earlier (24 or 48 weeks) and later (96 weeks) time points, with 95% confidence intervals on fold-change. Pairwise treatment groups were compared using Wilcoxon rank sum tests, with P values adjusted for false discovery rate control., Results: Changes in biomarkers varied by regimen during the 96 weeks of follow-up as follows: hsCRP declined with ATV/r and RAL, IL-6 declined only with RAL, and GLycA decreased in all groups. D-dimer declined with ATV/r and DRV/r and was unchanged with RAL. Markers of T-cell activation and sCD163 (but not sCD14 and CD14-+CD16+) declined in all groups., Conclusions: Despite some differences in specific markers of inflammation and immune activation between the antiretroviral therapy (ART) regimens, we found no consistent evidence that the reduction of inflammation and immune activation with ART initiation was different between RAL and PI-based regimens., Clinical Trials Registration: NCT00811954 and NCT00851799., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART., Methods: A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models., Results: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation., Conclusions: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)., Methods: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression., Results: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1)., Conclusions: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation., Clinical Trials Registration: NCT 00811954., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown., Methods: The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed., Results: Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4(+) cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32-8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40-8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15-.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression., Conclusions: For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The relationships between soluble CD14 (sCD14), endotoxin (lipopolysaccharide [LPS]), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection., Methods: We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group [ACTG] 5078), where subjects were enrolled as risk factor-controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)-based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (ΔCIMT)., Results: In multivariate analysis of the HIV-infected subjects, each 1 µg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 µm/y (95% confidence interval, .07-2.98; P = .04) in the ΔCIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 µm/y (95% confidence interval, .18-.81; P = .003) in the ΔCIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ΔCIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1)., Conclusions: Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.