Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.

Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context.

Widespread use of contemporary antiretroviral therapy globally has transformed HIV disease into a chronic illness associated with excess risk for disorders of the heart and circulatory system. Current clinical care and research has focused on improving HIV-related cardiovascular disease outcomes, survival, and quality of life. In high-income countries, emphasis on prevention of atherosclerotic coronary artery disease over the past decade, including aggressive management of traditional risk factors and earlier initiation of antiretroviral therapy, has reduced risk for myocardial infarction among persons living with human immunodeficiency virus-1 infection. Still, across the globe, persons living with human immunodeficiency virus-1 infection on effective antiretroviral therapy treatment remain at increased risk for ischemic outcomes such as myocardial infarction and stroke relative to the persons without HIV. Unique features of HIV-related cardiovascular disease, in part, include the pathogenesis of coronary disease characterized by remodeling ectasia and unusual plaque morphology, the relative high proportion of type 2 myocardial infarction events, abnormalities of the aorta such as aneurysms and diffuse aortic inflammation, and HIV cerebrovasculopathy as a contributor to stroke risk. Literature over the past decade has also reflected a shift in the profile and prevalence of HIV-associated heart failure, with a reduced but persistent risk of heart failure with reduced ejection fraction and a growing risk of heart failure with preserved ejection fraction. Cardiac magnetic resonance imaging and autopsy data have emphasized the central importance of intramyocardial fibrosis for the pathogenesis of both heart failure with preserved ejection fraction and the increase in risk of sudden cardiac death. Still, more research is needed to better characterize the underlying mechanisms and clinical phenotype of HIV-associated myocardial disease in the current era. Across the different cardiovascular disease manifestations, a common pathogenic feature is that HIV-associated inflammation working through different mechanisms may amplify underlying pathology because of traditional risk and other host factors. The prevalence and phenotype of individual cardiovascular disease manifestations is ultimately influenced by the degree of injury from HIV disease combined with the profile of underlying cardiometabolic factors, both of which may differ substantially by region globally.

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

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

A Pilot Randomized Controlled Trial of an mHealth Intervention to Improve PrEP Adherence Among Young Sexual Minority Men.

This randomized controlled study assessed the feasibility, acceptability, and preliminary impact of the PrEP iT! mHealth intervention designed to improve PrEP adherence among young men who have sex with men (YMSM). A national sample of 80 YMSM in the U.S. (Mage = 25 years; 54% racial/ethnic minority), recruited through social media ads, were randomized to either the PrEP iT! or usual PrEP care conditions. Participants completed online surveys and submitted self-collected dried blood sample (DBS) data as measures of PrEP adherence. Differences in PrEP adherence across treatment arms and between participants with high versus low engagement in PrEP iT! were assessed. Retention was high at the three (94%) and six (93%) month assessment, and participants in PrEP iT! reported satisfactory acceptability of the intervention. There were no significant differences in self-reported or DBS-derived PrEP adherence between randomized groups. However, YMSM in the PrEP iT! group with high PrEP adherence (the equivalent of four or more doses/week through self-report and DBS-derived measures) demonstrated significantly higher engagement in the intervention than those with low PrEP adherence (the equivalent of 3 or fewer doses/week). Overall, the PrEP iT! intervention demonstrated strong feasibility and acceptability. The finding that high PrEP iT! intervention engagement was associated with protective levels of PrEP adherence suggests it is a viable adherence support tool that should be further evaluated in definitive trial among YMSM who need basic support, or as part of a more comprehensive adherence support package for those who need greater assistance.Trial registration Clinical Trials # NCT04509076 (registered August 10, 2020).

Investigation of Causal Effects of Protein Biomarkers on Cardiovascular Disease in Persons With HIV.

BACKGROUND: There is an incompletely understood increased risk for cardiovascular disease (CVD) among people with HIV (PWH). We investigated if a collection of biomarkers were associated with CVD among PWH. Mendelian randomization (MR) was used to identify potentially causal associations. METHODS: Data from follow-up in 4 large trials among PWH were used to identify 131 incident CVD cases and they were matched to 259 participants without incident CVD (controls). Tests of associations between 460 baseline protein levels and case status were conducted. RESULTS: Univariate analysis found CLEC6A, HGF, IL-6, IL-10RB, and IGFBP7 as being associated with case status and a multivariate model identified 3 of these: CLEC6A (odds ratio [OR] = 1.48, P = .037), HGF (OR = 1.83, P = .012), and IL-6 (OR = 1.45, P = .016). MR methods identified 5 significantly associated proteins: AXL, CHI3L1, GAS6, IL-6RA, and SCGB3A2. CONCLUSIONS: These results implicate inflammatory and fibrotic processes as contributing to CVD. While some of these biomarkers are well established in the general population and in PWH (IL-6 and its receptor), some are novel to PWH (HGF, AXL, and GAS6) and some are novel overall (CLEC6A). Further investigation into the uniqueness of these biomarkers in PWH and the role of these biomarkers as targets among PWH is warranted.

HIV-PASS (Pain and Sadness Support): Randomized Controlled Trial of a Behavioral Health Intervention for Interference Due to Pain in People Living With HIV, Chronic Pain, and Depression.

OBJECTIVE: This study aimed to determine whether HIV-Pain and Sadness Support (HIV-PASS), a collaborative behavioral health intervention based on behavioral activation, is associated with decreased pain-related interference with daily activities, depression, and other outcomes in people living with HIV. METHODS: We conducted a three-site clinical trial ( n = 187) in which we randomly assigned participants to receive either HIV-PASS or health education control condition. In both conditions, participants received seven intervention sessions, comprising an initial in-person joint meeting with the participant, their HIV primary care provider and a behavioral health specialist, and six, primarily telephone-based, meetings with the behavioral health specialist and participant. The intervention period lasted 3 months, and follow-up assessments were conducted for an additional 9 months. RESULTS: Compared with health education, HIV-PASS was associated with significantly lower pain-related interference with daily activities at the end of month 3 (our primary outcome; b = -1.31, 95% confidence interval = -2.28 to -0.34). We did not observe other differences between groups at 3 months in secondary outcomes that included worst or average pain in the past week, depression symptoms, anxiety, and perceived overall mental and physical health. There were no differences between groups on any outcomes at 12 months after enrollment. CONCLUSIONS: A targeted intervention can have positive effects on pain interference. At the end of intervention, effects we found were in a clinically significant range. However, effects diminished once the intervention period ended. TRIAL REGISTRATION: ClinicalTrials.gov NCT02766751.

The Use of Daily and On-Demand Oral Pre-Exposure Prophylaxis Dosing Strategies Among Young Adult Gay, Bisexual and Other Men who have Sex with Men Enrolled in an mHealth Adherence Intervention.

Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention option for gay, bisexual and other men who have sex with men (GBMSM). However, with newer PrEP options, a greater understanding of whether and why GBMSM switch dosing strategies is needed to inform clinical practice and research. We assessed the dosing strategies (daily or on-demand) of GBMSM enrolled in an mHealth PrEP adherence pilot intervention at four timepoints over approximately 10 months. Among GBMSM with complete data (n = 66), a consistent daily dosing strategy was used by most (73%) participants across all time points, while on-demand PrEP was used at least once during the study period by 27% of participants. A higher percentage of on-demand PrEP users self-reported as Asian/Pacific Islander and had less positive attitudes toward PrEP, adjusting for key sociodemographic variables and intervention arm. Daily PrEP users reported high numbers of sexual partners, and the primary reason that they would switch to on-demand PrEP is reduced sexual activity. At the final assessment, 75% of participants were taking daily PrEP, of whom 27% reported that they would like to switch to another option, including on-demand and long-acting injectable PrEP. While findings were largely descriptive, they showed that switches in PrEP dosing strategies are relatively common and PrEP strategy choice may vary across racial and ethnic groups.

Strategies Used to Manage Chronic Pain in HIV-Disease: Comparing Persons Prescribed Opioids Versus Persons not Receiving Opioids.

Chronic pain is common in people living with HIV (PLWH), causes substantial disability and is associated with limitations in daily activities. Opioids are commonly prescribed for pain treatment among PLWH, but evidence of sustained efficacy is mixed. There is little information available on how PLWH who have chronic pain use multimodal strategies in pain management. The current cross-sectional study examined background characteristics, self-reported pain, and the use of other pain treatments among 187 PLWH with chronic pain and depressive symptoms who were and were not prescribed opioids. Approximately 20.9% of participants reported using prescription opioids at the time of the study interview. These individuals were significantly more likely to report having engaged in physical therapy or stretching, strengthening or aerobic exercises in the previous 3 months, recent benzodiazepine use, and receiving disability payments. There were no significant differences in pain characteristics (pain-related interference, average pain severity, and worst pain severity) between the two groups. Those not prescribed opioids were more likely to report better concurrent physical functioning and general health, and fewer physical role limitations, but higher depression symptom severity. Our findings suggest that many PLWH with chronic pain and depressive symptoms express high levels of pain with deficits in physical function or quality of life despite their use of opioids. The high rate of co-use of opioids and benzodiazepines (30.8%) is a concern because it may increase risk of overdose. An integrated care approach that includes a variety of effective non-pharmacologic treatment strategies such as physical therapy may be beneficial in reducing the reliance on opioids for pain management.

Anger and substance use in HIV-positive patients with chronic pain.

Chronic pain increases the risk of substance use in people living with HIV (PLWH). Depression and anxiety have also been identified as risk factors for substance use among PLWH. Relatedly, other negative mood states, such as anger, may influence chronic pain among PLWH. The current cross-sectional study examined whether the distinct negative mood state of anger is associated with substance use among 187 PLWH who report chronic pain. Using negative binomial regression analyses, we found higher levels of anger were positively associated with alcohol use. Higher levels of anger were inversely associated with benzodiazepine use. No association was found between anger and marijuana use, and there were no significant interactions between anger and pain severity on substance use. Our findings suggest that anger is an independent risk factor for substance use among PLWH and chronic pain. Addressing anger may be useful when adapting behavioral therapies in the treatment of pain among PLWH.

The relationship between substance use and physical activity among people living with HIV, chronic pain, and symptoms of depression: a cross-sectional analysis.

ABSTRACTChronic pain, depression, and substance use are common among people living with HIV (PLWH). Physical activity can improve pain and mental health. Some substances such as cannabis may alleviate pain, which may allow PLWH to participate in more physical activity. However, risks of substance use include poorer mental health and HIV clinical outcomes. This cross-sectional analysis examined the relationships of self-reported substance use (alcohol, cannabis, and nicotine use), gender, and age with self-reports of walking, moderate physical activity, and vigorous physical activity, converted to Metabolic Equivalent of Task Units (METs), among 187 adults living with HIV, chronic pain, and depressive symptoms in the United States. Women reported less walking, vigorous activity, and total physical activity compared to men. Individuals who used cannabis reported more vigorous physical activity relative to those who did not use cannabis. These findings were partially accounted for by substance use*gender interactions: men using cannabis reported more vigorous activity than all other groups, and women with alcohol use reported less walking than men with and without alcohol use. Research is needed to increase physical activity among women who use substances and to evaluate reasons for the relationship between substance use and physical activity among men.

Attitudes Toward and Beliefs in the Effectiveness of Biomedical HIV Prevention Strategies Among Emerging and Young Adult Sexual Minority Men.

BACKGROUND: Pre-exposure prophylaxis (PrEP) and HIV treatment as prevention, which underlies the Undetectable = Untransmittable (U = U) campaign, are two effective biomedical approaches for HIV prevention among sexual minority men (SMM). Attitudes toward PrEP and U = U may differ between SMM emerging adults (EA: 18-24 years old) and young adults (YA: 25-29 years old) to drive differences in sexual behavior. However, to date, few studies assessed the degree to which YAs and EAs differ in their beliefs in the effectiveness of PrEP and U = U. METHOD: A national sample of 80 SMM in the USA (Mage = 25.1 years; 53.7% racial/ethnic minority; 38.8% EA; 61.3% YA) participated in a 6-month mHealth intervention for PrEP adherence. Non-parametric tests assessed differences in sexual behaviors and attitudes toward the effectiveness of PrEP and U = U between EAs and YAs using baseline data. RESULTS: Compared to EAs, higher proportions of YAs trusted PrEP's effectiveness and considered condom use unnecessary after taking PrEP. More YAs than EAs were willing to engage in sexual behaviors that they felt too risky before learning about U = U and were more comfortable having condomless sex with HIV-positive partners. Conversely, a greater proportion of EAs than YAs preferred to use condoms even when their partners are on anti-HIV medications. CONCLUSION: Overall, YAs trusted the effectiveness of U = U and PrEP more than EAs, underscoring developmental differences in SMM's perspectives on biomedical HIV prevention tools. Our findings underscore the importance of tailoring messages on biomedical HIV prevention options differently for EAs and YAs to optimize uptake.

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

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multicenter trial. PATIENTS: Hospitalized patients with COVID-19 without end-organ failure. INTERVENTION: Bamlanivimab (7000 mg) or placebo. MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections). RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs. LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed. CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

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

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

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

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

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

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.

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

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

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

PURPOSE OF REVIEW: This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART). RECENT FINDINGS: We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways. SUMMARY: Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4 T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH.

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

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCE The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

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

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

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

OBJECTIVE: The aim of this study was to determine the concordance of self- and clinician-collected anorectal swabs for the detection of human papillomavirus (HPV) DNA in a population of HIV-negative men who have sex with men (MSM). METHODS: This cross-sectional study involved recruitment of HIV-negative MSM in a Midwestern US metropolitan area to collect paired sequential self- and clinician-collected anorectal swabs using illustrated instructions. Swabs were tested for type-specific HPV DNA with a comparison of type-specific HPV categories detected by each method. The sensitivity and specificity of self-collection were calculated assuming clinician collection as the criterion standard. McNemar's test and κ statistics were used to determine percent agreement and concordance of self- and clinician-collected swab results. RESULTS: Seventy-eight participants had paired anorectal swab samples of adequate quality for analyses. The sensitivity and specificity of self-collected swabs for detection of all high-risk HPV DNA types were 69.8% and 91.4%, respectively. Similar degrees of sensitivity and specificity of self-collection were seen for other groups of high-risk HPV types. Percent agreement and κ statistic for self- and clinician-collected swabs for all high-risk HPV types were 80.8% and 0.53, respectively. CONCLUSIONS: Self-collected anorectal swab samples showed lower sensitivity but moderate to high specificity for detection of high-risk and vaccine-preventable HPV types compared with clinician-collected swab samples. Self-collection instructional details and the thoroughness of clinician collection of samples may have impacted sensitivity and specificity, suggesting a need to optimize and standardize instructions.