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Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons. We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models. In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001). In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.

Current cell-based assays for determining the functional properties of high-density lipoproteins (HDL) have limitations. We report here the development of a new, robust fluorometric cell-free biochemical assay that measures HDL lipid peroxidation (HDLox) based on the oxidation of the fluorochrome Amplex Red. HDLox correlated with previously validated cell-based (r = 0.47, p

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.

BackgroundWomen who use antiretroviral therapy (ART) solely for the prevention of mother-to-child transmission of HIV discontinue postpartum. We hypothesized that women discontinuing ART by 6 weeks postpartum ("discontinuers") would have elevated postpartum inflammatory biomarker levels relative to women remaining on ART postpartum ("continuers").MethodsData from HIV-infected pregnant women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 with CD4 counts >350 cells per cubic millimeter before initiating ART or first pregnancy CD4 counts >400 cells per cubic millimeter after starting ART and with available stored plasma samples at >20 weeks of gestation, delivery, and 6 weeks postpartum were analyzed. Plasma samples were tested for highly sensitive C-reactive protein, D-dimer, and interleukin-6. We used longitudinal linear spline regression to model biomarkers over time.ResultsData from 128 women (65 continuers and 63 discontinuers) were analyzed. All biomarkers increased from late pregnancy to delivery, then decreased postpartum (slopes different from 0, P < 0.001). Continuers had a steeper decrease in log D-dimer between delivery and 6 weeks postpartum than discontinuers (P = 0.002).ConclusionsIn contrast to results from treatment interruption studies in adults, both ART continuers and ART discontinuers had significant decreases in the levels of D-dimer, highly sensitive C-reactive protein, or interleukin-6 postpartum. Continuation was associated with a more rapid decline in D-dimer levels compared with discontinuation.

Abstract Background HDL function rather than absolute level may be a more accurate indicator for risk of developing atherosclerosis. Dysfunctional HDL has increased redox activity and reduced antioxidant properties, but it is unknown whether abnormal HDL function is associated with progression of atherosclerosis in HIV-1-infected subjects. Findings We retrospectively measured serum HDL function in 91 subjects from a prospective 3-year study of carotid artery intima-media thickness (CIMT), which enrolled triads of risk factor-matched persons that were HIV-1-uninfected (n=36) or HIV-1+ with (n=29) or without (n=26) protease inhibitor (PI)-based therapy for ≥ 2 years. HDL function was assessed using a biochemical assay that measures the oxidation of dihydrorhodamine 123 (DHR oxidation rate, DOR), in which higher DOR readout corresponds to dysfunctional HDL phenotype.There were no significant associations between DOR and HIV-1 infection. In univariate analysis of 55 HIV-1-infected subjects, greater waist circumference and lower serum HDL were significantly associated with higher baseline levels of DOR (p=0.01). These subjects had significant increases in levels of DOR over time (3 years) that were associated with white race (p=0.03), higher nadir CD4 count (p0.1) (DOR), were significantly associated (p=0.02) with progression of CIMT. Conclusion In a small matched cohort study of HIV-1-infected subjects who had a low cardiovascular risk profile, HDL function changed over time and was independently associated with anthropometric parameters of obesity but not with progression of CIMT.

Studies with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) monoinfection and HIV coinfection were highlighted at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI). In HCV monoinfected patients, several interferon alfa-sparing, all-oral regimens demonstrated cure rates of greater than 90% with 12 weeks of treatment, including for hard-to-treat patients. Cure rates of 75% were attained in HIV/HCV coinfected patients with the addition of the investigational HCV protease inhibitor (PI) simeprevir to peginterferon alfa and ribavirin. Drug-drug interaction data to inform safe coadminstration of antiretroviral therapy with DAA-based HCV treatment were presented. There was continued emphasis on pathogenesis, management, and prevention of the long-term complications of HIV disease and its therapies, including cardiovascular disease, renal disease, alterations in bone metabolism, and vitamin D deficiency, along with a growing focus on biomarkers to predict development of end-organ disease. Understanding the elevated risk for non-AIDS-defining malignancies in the HIV-infected population and optimal management was a focal point of this year's data. Finally, the conference provided important information on tuberculosis coinfection and cryptococcal meningitis.

BackgroundVisceral adiposity in the setting of HIV infection and antiretroviral therapy (ART) is not fully understood, and treatment options remain limited. Telmisartan, an angiotensin receptor blocker and partial PPAR-γ agonist, has been shown to decrease visceral fat and improve metabolic and inflammatory parameters in HIV-uninfected subjects.MethodsHIV-infected subjects with HIV-1 RNA 94/95 cm or waist: hip ratio >0.88/0.94 received open-label telmisartan 40 mg po daily for 24 weeks. Adipose tissue (AT) volumes were quantified by L4-L5 single slice computed tomography. Metabolic and inflammatory markers were obtained fasting. Thirty-five subjects provided 80% power to detect a 10% 24-week decrease in visceral AT (VAT, two-sided α = 0.05).ResultsThirty-five subjects enrolled and completed the protocol. At entry (median or %): age 49 years, 43% female, 77% non-white, 91% non-smokers, CD4+ T cell count 590 cells/mm(3), BMI 31 kg/m(2). AT responses were heterogeneous, with statistically significant losses of median (IQR) total (TAT, 2.9% (-9.8, 0.7), p = 0.03) and subcutaneous (SAT, -2.7% (-9.8, 1.1), p = 0.03) AT, but not VAT (-2.7% (-20.5, 14.2), p = 0.53). Significant decreases in waist circumference and waist:hip ratio occurred (both p

Studies on the efficacy of and drug interactions with the hepatitis C virus (HCV) direct-acting antivirals (DAAs) in HCV/ HIV coinfection were a highlight of the 2012 Conference on Retroviruses and Opportunistic Infections. The addition of an HCV protease inhibitor (PI) to pegylated interferon alfa/ribavirin increased HCV cure rates by 30% to 35% in HCV genotype 1 treatment-naive HIV-coinfected patients, an increase similar to that observed in HIV-uninfected HCV-infected patients. Drug interactions with antiretrovirals can be complex, and DAAs are recommended for use only with antiretroviral drugs for which pharmacokinetic data are available. Further drug interaction and clinical data are needed to ensure the safe coadminstration of DAAs with antiretroviral therapy. The conference placed continued emphasis on pathogenesis, management, and prevention of the long-term complications of HIV disease and its therapies, including cardiovascular disease, lipodystrophy, renal disease, alterations in bone metabolism, and vitamin D deficiency, along with a growing focus on biomarkers to predict development of end-organ disease. HIV has increasingly been recognized as a disease of accelerated aging, manifested by increased progression of vascular disease, cellular markers of aging, and a heightened risk of certain non-AIDS-defining malignancies. This year's conference also highlighted data on diagnosis, prevention, and complications of tuberculosis coinfection as well as the treatment and prevention of coinfections that are common with HIV, including cryptococcal meningitis, influenza, and varicella zoster.

HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population.

Abstract Background The role of pro-inflammatory lipids in systemic immune activation in HIV infection remains largely unknown. We hypothesized that HIV-1-infected persons on antiretroviral therapy would have pro-inflammatory high density lipoprotein (HDL), and that an apoA-1 mimetic peptide might reverse the inflammatory properties of HDL in these persons. Methods Plasma was obtained from 10 HIV-1-infected individuals on combination antiretroviral therapy with suppressed viremia and was incubated with the apoA-I mimetic peptide L-4F or sham-treated prior to isolation of HDL. The HDL that was isolated from each sample was tested for its ability to inhibit LDL-induced MCP-1 production in cultures of human aortic endothelial cells. Results We found in a small pilot study of HIV-1-infected individuals with suppressed viremia on combination antiretroviral therapy that oxidative stress and inflammation in HIV-1 are associated with a marked reduction of HDL antioxidant/anti-inflammatory activities. In vitro, these abnormalities were significantly improved by treatment with the apoA-1 mimetic peptide, 4F. Conclusions These preliminary observations suggest that the anti-inflammatory properties of HDL are defective in HIV-1-infected persons despite treatment that is considered to be virologically successful.

BackgroundFifty percent of people living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) worldwide are female. In Brazil, for example, 240,000 women are infected with HIV, rates of infection in women have increased over the last two decades, and addressing HIV prevention and treatment for women at risk for, or living with, HIV/AIDS remains a challenge. To better address the needs of women living with HIV in Brazil, the Instituto de Pesquisa Clínica Evandro Chagas - Fundação Oswaldo Cruz (IPEC-FIOCRUZ) HIV Women's Cohort was established in 1996 to study the natural history of women seeking HIV care. This analysis describes the characteristics of women in the cohort who participated in HIV clinical trials between 1999 and 2008.MethodsA total of 736 Women's Cohort participants were in active follow-up and 665 participants from the Women's Cohort were included in univariable and multivariable analyses to determine socioeconomic and sociodemographic factors associated with women's participation in HIV clinical trials at our site.ResultsOf the complete cohort, 23% participated in a clinical trial between January 1999 and July 2008. Odds of participation decreased for women who were younger than 35 years old, currently employed, had an HIV-positive sexual partner, and/or who reported a lifetime history of illicit drug use. Alternatively, the odds of participation increased for women who had more than 8 years of formal education, were living independently, and/or were married or cohabitating.ConclusionThe rate of participation in HIV clinical trials by women in the IPEC-Fiocruz Cohort was similar to other published cohorts, but identification of local risk factors and barriers to participation remains important. Our analysis offers a novel description of the factors associated with participation in HIV clinical trials among women in care at IPEC-FIOCRUZ in Rio de Janeiro, Brazil.

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]