Vulnerability in Biomedical Research: A Historical Reflection and Practical Implications for HIV Cure-Related Research.

The concept of vulnerability in bioethics was first referenced in 1979, when the Belmont Report highlighted the need for special consideration of certain populations in the application of its general principles of respect for persons, beneficence, and justice in research with human participants. Since then, a body of literature has emerged regarding the content, status, and scope, as well as ethical and practical implications of vulnerability in biomedical research. The social history of HIV treatment development has at various points reflected and actively influenced bioethics' debate on vulnerability. In the late 1980s and early 1990s, people with AIDS activist groups drafted landmark patient empowerment manifestos like The Denver Principles, fighting to have greater involvement in the design and oversight of clinical trials related to HIV treatment, and in doing so, pushed against research ethics protocols created with the intention of protecting vulnerable populations. The determination of appropriate benefit/risk profiles in clinical trials was no longer limited to the purview of clinicians and scientists, but began to include the perspectives of people with HIV (PWH) and affected communities. In contemporary HIV cure-related research, where participants often risk health for no personal clinical benefit, the community's voiced motivations and objectives for participation continue to challenge population-based accounts of vulnerability. While the development of a framework for discussion and the establishment of clear regulatory requirements are necessary to support the practical and ethical conduct of research, they risk distraction from the fundamental value of voluntary participation and potentially overlook the unique history and perspectives of PWH in their participation in the quest toward an HIV cure.

People with HIV at the end-of-life and their next-of-kin/loved ones are willing to participate in interventional HIV cure-related research.

INTRODUCTION: The Last Gift study at the University of California San Diego (UCSD), United States enrolls terminally ill people with HIV (PWH) in HIV cure research. METHODS: From 2017 to 2022, we conducted surveys with Last Gift participants and their next-of-kin/loved ones to evaluate willingness to participate in different types of HIV cure research at the end of life (EOL). We analyzed willingness data descriptively. RESULTS: We surveyed 17 Last Gift participants and 17 next-of-kin/loved ones. More than half of Last Gift participants ( n  = 10; 58.8%) expressed willingness to participate in studies involving totally new treatments or approaches ('first-in-human' studies), a combination of different approaches, the use of unique antibodies, proteins or molecules, or therapeutic vaccines. Under one-quarter of Last Gift participants ( n  = 4; 23.5%) expressed willingness to participate in research involving interventions that may shorten their life expectancy to benefit medical research. Most Last Gift participants and their next-of-kin/loved ones also expressed high acceptance for various types of donations and biopsies at the EOL (e.g. hair donations and skin, lymph node or gut biopsies). DISCUSSION: Knowing whether people would be willing to participate in different types of EOL HIV cure research can help inform the design of future innovative studies. As a research community, we have a duty to design studies with adequate safeguards to preserve the public trust in research and honor PWH's important gift to humanity.

Distinct effects of SSRIs and SNRIs on Soluble Biomarkers in Blood and Cerebrospinal Fluid of people with HIV.

BACKGROUND: Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immuno-modulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. METHODS: Cross-sectional single-center (U.S.) analysis in 184 PWH on ART with plasma HIV RNA < 200 cp/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and and clinical conditions. RESULTS: Participants were mostly middle-aged men, with median CD4+ T-cells of 620/µL. In adjusted models, SSRI use was associated with three PCs: higher CSF and plasma Aß42 and CSF CCL2 (aß=0.14, p = 0.040); lower CSF 8-oxo-dG, total tau, and sCD14 (aß=-0.12, p = 0.042); higher plasma sCD14 with lower sCD40L (aß=0.15, p = 0.042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aß=0.22, p = 0.004). Statins and ACEIs showed no association. CONCLUSIONS: SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH.

Elevated Plasma Protein Carbonyl Concentration Is Associated with More Abnormal White Matter in People with HIV.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

Perceived risks and benefits of enrolling people with HIV at the end of life in cure research in Southern California, United States.

Introduction: Although current antiretroviral therapy allows most people with HIV (PWH) to experience normal longevity with a good quality of life, an HIV cure remains elusive due to HIV reservoir formation within deep tissues. An HIV cure remains highly desirable to the community of PWH. This study reports on the perceived risks and benefits of participation in the Last Gift study, a study aimed at characterizing HIV reservoirs via post-mortem autopsy, among PWH at the end of life (EOL) and their next-of-kin (NOK)/loved ones. Methods: Last Gift participants (PWH with a terminal illness and/or near the end of life) and their NOK/loved ones were surveyed for perceptions of risks, benefits, and meaning for participation in the Last Gift study. Results: The average age of the 17 Last Gift participants was 66.6 years, 3 were females, 1 person identified as Hispanic, and 15 as Caucasian. The average age of the 17 NOK/loved ones was 56.7 years, and relationships to Last Gift participants included partner/spouse, sibling, friend, child, parent, grandparent, and nephew. The only perceived personal risk of the Last Gift among participants was the blood draws (3/17). NOK/loved ones perceived the following risks: blood draws (2/17), physical pain (3/17), worry that something bad will happen (2/17), and unpleasant side effects (1/17). Participants in Last Gift and NOK/loved ones indicated the study had various positive social effects. For both participants and NOK/loved ones, the most frequent perceived personal benefit of the Last Gift was the satisfaction of supporting HIV cure research. Discussion: Participants perceived minimal personal and societal risks and valued the altruistic benefits of participating in the Last Gift study. Last Gift participants and NOK/loved ones were cautious about possible personal risks of EOL HIV cure research but still viewed that the emotional, psychological and societal benefits of participation outweighed potential risks.

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program.

PURPOSE OF REVIEW: Deep tissue HIV reservoirs, especially within the central nervous system (CNS), are understudied due to the challenges of sampling brain, spinal cord, and other tissues. Understanding the cellular characteristics and viral dynamics in CNS reservoirs is critical so that HIV cure trials can address them and monitor the direct and indirect effects of interventions. The Last Gift program was developed to address these needs by enrolling altruistic people with HIV (PWH) at the end of life who agree to rapid research autopsy. RECENT FINDINGS: Recent findings from the Last Gift emphasize significant heterogeneity across CNS reservoirs, CNS compartmentalization including differential sensitivity to broadly neutralizing antibodies, and bidirectional migration of HIV across the blood-brain barrier. Our findings add support for the potential of CNS reservoirs to be a source of rebounding viruses and reseeding of systemic sites if they are not targeted by cure strategies. This review highlights important scientific, practical, and ethical lessons learned from the Last Gift program in the context of recent advances in understanding the CNS reservoirs and key knowledge gaps in current research.

The impact of changing reflexive to clinician-ordered Clostridioides difficile polymerase chain reaction (PCR) testing for indeterminate cases: Cost savings without associated adverse events.

OBJECTIVE: To evaluate changing Clostridioides difficile infection (CDI) testing among inpatients with indeterminate enzyme immunoassay (EIA) results (antigen+/toxin-) from reflexive polymerase chain reaction (PCR) testing to clinician-ordered PCR testing. DESIGN: Multicenter, before-and-after, quasi-experimental study. SETTING: Four large urban tertiary-care hospitals. METHODS: We evaluated two 6-month periods before and after an intervention. The primary study outcome was the change in the number of CDI diagnoses between periods. Secondary outcomes included the number of PCR tests performed, adverse events, and healthcare cost savings. RESULTS: In total, 500 EIA-indeterminate C. difficile test results were evaluated: 281 before the intervention and 219 thereafter. CDI was diagnosed by PCR among EIA-indeterminate cases in 182 in the preintervention period versus 94 patients in the postintervention period (48% reduction; P < .01). PCR testing was performed in 99.6% of indeterminate cases (280 of 281; 1 not performed due to an inhibitor) in the preintervention period versus 66% (144 of 219) in the postintervention period (34% reduction; P < .01). We observed no differences between study periods in 30-day all-cause (P = .96), GI-related (P = .93), or C. difficile (P = .47) readmissions, nor in 30-day C. difficile infections (P > .99). No patient without a PCR test in the postintervention period and not treated was later diagnosed with CDI. Each reflexive PCR test not performed led to a cost savings of $4,498 per patient. CONCLUSIONS: Applying diagnostic stewardship to C. difficile PCR testing in the inpatient setting led to significant reductions in both testing and cases. Changing the C. difficile PCR testing algorithm for EIA-indeterminate cases from reflexive to clinician-required ordering resulted in valuable cost savings without associated adverse events.

Absence of neurocognitive impairment in a large Chinese sample of HCV-infected injection drug users receiving methadone treatment.

BACKGROUND: Prior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances. METHODS: We administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n=169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU- group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population. RESULTS: The IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance. CONCLUSION: Failure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal.

Co-morbidities in persons infected with HIV: increased burden with older age and negative effects on health-related quality of life.

This study sought to determine the synergistic effects of age and HIV infection on medical co-morbidity burden, along with its clinical correlates and impact on health-related quality of life (HRQoL) across the lifespan in HIV. Participants included 262 individuals across four groups stratified by age (≤40 and ≥50 years) and HIV serostatus. Medical co-morbidity burden was assessed using a modified version of the Charlson Co-morbidity Index (CCI). Multiple regression accounting for potentially confounding demographic, psychiatric, and medical factors revealed an interaction between age and HIV infection on the CCI, with the highest medical co-morbidity burden in the older HIV+cohort. Nearly half of the older HIV+group had at least one major medical co-morbidity, with the most prevalent being diabetes (17.8%), syndromic neurocognitive impairment (15.4%), and malignancy (12.2%). Affective distress and detectable plasma viral load were significantly associated with the CCI in the younger and older HIV-infected groups, respectively. Greater co-morbidity burden was uniquely associated with lower physical HRQoL across the lifespan. These findings highlight the prevalence and clinical impact of co-morbidities in older HIV-infected adults and underscore the importance of early detection and treatment efforts that might enhance HIV disease outcomes.

Risks and predictors of current suicidality in HIV-infected heroin users in treatment in Yunnan, China: a controlled study.

OBJECTIVE: Suicide is an important public health problem in China. Elsewhere, injection drug use and HIV infection have independently been associated with suicidality, but research has often overlooked these high-risk groups in China. We determined the frequency and predictors of suicidal ideas in Chinese HIV-infected (HIV(+)) and HIV-uninfected (HIV(-)) heroin injection drug users (IDUs) in treatment and a control sample. We hypothesized that rates of suicidal ideas would be significantly higher among IDUs compared with controls and highest among HIV IDUs. METHOD: We assessed suicidal ideas within the past 2 weeks in HIV(+) (n = 204) and HIV(-) (n = 202) heroin IDUs in methadone treatment in Yunnan, a province at the intersection of the heroin and HIV epidemics, and in demographically matched HIV non-drug-using controls (n = 201). RESULTS: Rates of suicidality were higher in IDUs than controls, but there was no additive effect of HIV infection (HIV(+) IDU: 43.1%; HIV(-) IDU: 37.1%; controls: 8.5%). Among HIV(+) IDUs, suicidality was associated most strongly with a combination of prior history of major depression, low perceived social support, and experience of HIV-relevant stress, but not with AIDS diagnosis. Among HIV(-) IDUs, suicidality was associated with prior history of major depressive or alcohol use disorder. Less than 25% of IDUs with suicidality had histories of mood or alcohol use diagnoses. CONCLUSION: Because suicidal ideation is frequent in IDUs in China, regardless of HIV status, and is not fully accounted for by past psychiatric history, additional research may be warranted.

Approaches to identifying appropriate medication adherence assessments for HIV infected individuals with comorbid bipolar disorder.

Assessing medication adherence in already difficult-to-treat HIV-infected subpopulations presents a unique challenge. The objective of this study was to compare different approaches to assessing medication adherence: (1) electronic medication monitoring, (2) standardized self-report questionnaire, and (3) self-report visual analogue scale, and to determine whether antiretroviral therapy (ART) adherence measures differed for HIV-infected persons with bipolar disorder (HIV+ /BD+) as compared to HIV-infected persons without bipolar disorder (HIV+ /BD-). ART adherence was assessed for 74 HIV-positive participants using the Medication Event Monitoring System (MEMS), AIDS Clinical Trials Group (ACTG) adherence questionnaire, and visual analogue scale (VAS). Participants were classified as adherent or nonadherent on each measure by previously validated cutscores. Correlations and logistic regressions were used to examine associations between adherence measures and demographic and clinical variables. In the HIV+ /BD- group, significant correlations existed between each self-report measure and the MEMS. Males comprised 81% of the study population. Participants averaged 44 years of age and 13 years of education. No significant correlations were found among adherence measures in the HIV+ /BD+ group. Among participants reporting adherence on either self-report measure but classified as nonadherent based on MEMS, 94% had a diagnosis of bipolar disorder. Bipolar disorder was a significant predictor of adherence classification discordance among self-report measures. Our findings suggest that it remains difficult to assess ART adherence among HIV-positive individuals with bipolar disorder. Combined approaches of self-report and objective measures may be the best way to estimate adherence, and may provide the best basis for interventions designed to improve adherence in difficult-to-treat populations.

HIV-infected individuals with co-occurring bipolar disorder evidence poor antiretroviral and psychiatric medication adherence.

The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD- persons. Classification of adherent (≥ 90%) or non-adherent (<90%) based on proportion of correctly taken doses over 30 days was determined using electronic medication monitoring devices. HIV+/BD+ persons were significantly less likely to be ART adherent (47.7%) as compared to HIV+/BD- (90.9%) persons. Within the HIV+/BD+ group, mean psychiatric medication adherence was significantly worse than ART medication adherence, although there was a significant correlation between ART and psychiatric adherence levels. Importantly, 30-day ART adherence was associated with plasma virologic response among HIV+/BD+ individuals. Given the high overlap of HIV and BD, and the observed medication adherence difficulties for these persons, specialized adherence improvement interventions are needed.

A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men.

RATIONALE: The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones. OBJECTIVES: We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin. METHODS: In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo. RESULTS: Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels. CONCLUSION: These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.

Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy.

OBJECTIVE: in HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated. DESIGN: prospective, comparative, single-center, cross-sectional cohort study. METHODS: clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression. RESULTS: of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4-5.5). CONCLUSIONS: elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.

Cerebrospinal fluid human immunodeficiency virus viral load in patients with neurosyphilis.

Syphilis is a frequent coinfection with human immunodeficiency virus (HIV). Whereas systemic syphilis infection increases plasma HIV RNA levels (viral load; VL), effects of syphilis on cerebrospinal fluid (CSF) VL are unknown. We hypothesized that intrathecal immune activation in neurosyphilis would selectively increase CSF VL in coinfected patients. In this study, HIV-infected research subjects (N = 225) were categorized into three groups based on serum rapid plasma reagin (RPR), microhemaglutination for Treponema pallidum (MHA-TP) MHA-TP, and CSF VDRL: 23 with neurosyphilis (NS+; reactive serum RPR and MHA-TP and positive CSF VDRL); 42 with systemic syphilis but not neurosyphilis (Syph+; reactive serum RPR and MHA-TP; negative CSF VDRL), and 160 without syphilis (Syph-; nonreactive serum RPR). Plasma and CSF HIV VL were quantified by reverse transcriptase-ploymerase chain reaction (RT-PCR) (Amplicor, Roche) in log(10) copies/ml. To adjust for covariates previously shown to influence CSF HIV VL (i.e., plasma VL, CD4, pleocytosis, and highly active antiretroviral therapy [HAART]), multivariable linear regression was used. Lumbar punctures (LP) done for research purposes diagnosed 23 with neurosyphilis; most (83%) of these reported prior syphilis treatment. Among subjects with detectable plasma VL, CSF VL was highest in NS+, followed by Syph+ and Syph- (P =.006). This relationship was independent of the level of plasma VL or CSF pleocytosis. By contrast, among subjects with undetectable plasma HIV VL, CSF VLs were similar in the three syphilis subgroups (P = .50). Neurosyphilis may amplify intrathecal HIV replication, possibly through immune activation that persists even after syphilis treatment. Because elevated CSF VL is associated with subsequent neurocognitive decline, future studies should evaluate the impact of neurosyphilis on the course of central nervous system (CNS) HIV infection.