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

The availability of antiretroviral therapy (ART) has increased the life expectancy of people with HIV (PWH) and reduced the incidence of AIDS-associated malignancies, yet PWH have a significantly increased incidence...

As is known, CD4 cell count is a significant parameter predicting HIV progression, opportunistic infections and death in HIV-infected individuals, as well was an important indicator for initiating antiretroviral therapy (ART). In China's National Free Antiretroviral Treatment Program, people with HIV (PWH) on ART can receive a CD4 count test at least once every six months. Importantly, the baseline CD4 count (before ART initiation) is significantly correlated with ART and even prognosis, but the influence of the peak CD4 cell count on ART and/or clinical outcomes is still unknown. A retrospective study was conducted among 7965 PWH who received ART from October 2003 to September 2022 at Yunnan Infectious Disease Hospital. Clinical features and laboratory data were collected and analyzed by Chi-square test, univariate and multivariate Cox regression analysis. After elimination of confounding variables, multivariate Cox regression analysis was performed to identify survival-related factors. Of a total of 7965 PWH in the ART treatment cohort who met the inclusion and exclusion criteria, 7939 were finally included in the subsequent analyses. First, it was found that the proportion of clinical variables, including sex, age distribution, interval from diagnosis to ART initiation, marital status, and others, was significantly different between the living and dead groups (P < 0.05). Impressively, significantly more PWH had the higher level of baseline, peak and recent CD4 cell counts in the living group compared to those in the dead group. Due to multicollinearity effect, after excluding confounders, the following factors were found to be significantly associated with mortality by multivariate Cox regression analysis: (1) male sex (hazard ratio (HR) = 1.268 [1.032, 1.559]; P = 0.024); (2) time from HIV confirmation to ART initiation ≥ 6 months (HR = 1.962 [1.631, 2.360]; P < 0.001); (3) peak CD4 cell count: Peak CD4 < 100cells/µL group (HR = 16.093 [12.041, 21.508]; P < 0.001), 100cells/µL ≤ x < 200cells/µL group (HR = 7.904 [6.148, 10.160]; P < 0.001), 200cells/µL ≤ x < 350cells/µL group (HR = 3.166 [2.519, 3.980]; P < 0.001), 350cells/µL ≤ x < 500cells/µL group (HR = 1.668 [1.291, 2.155]; P < 0.001). Interestingly, patients in male, time from HIV confirmation to ART initiation ≥ 6 months, or peak CD4 count < 500 cells/µl had inferior clinical outcomes, in other word, a lower peak CD4 cell count significantly increased the risk of death, and peak CD4 cell was independent in predicting the overall survival of PWH. It is important to promote "early diagnosis and treatment of HIV" and regularly monitor CD4 levels in HIV/AIDS to evaluate the efficacy of ART and immune reconstitution, and optimize the ART regimen in time to further reduce the mortality of PWH.

Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV.All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P = .011; aOR for fibrosis: 3.7 [1.82-7.53], P < .001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P = .003), stavudine (aOR: 3.73 [1.69-8.2], P = .001), and indinavir (aOR: 3.86 [1.59-9.37], P = .003). These associations were not observed in overweight/obese PHIV. Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV.

Risk factors for progression from prediabetes mellitus (pre-DM) to diabetes mellitus (DM) among people with HIV (PWH) receiving modern antiretroviral therapy (ART) require better characterization. AIDS Clinical Trials Group (ACTG) A5322 (HAILO) was an observational cohort study of PWH ≥40 years old. Participants initiated ART through ACTG randomized clinical trials. We used Cox proportional hazards regression models to identify risk factors for development of DM among HAILO participants with pre-DM. Among 1035 HAILO participants, 74 (7%) had pre-DM at entry and another 679 (66%) developed pre-DM during follow-up. Of 753 PWH with pre-DM, 167 (22%) developed DM. In multivariable models, the risk of developing DM was greater with higher BMI, lower CD4 count (≤200 cells/mm 3 ), hypertriglyceridemia, or higher waist circumference at pre-DM diagnosis ( P < 0.01). Rates of pre-DM and progression to DM remain high among virally suppressed PWH receiving modern ART regimens. Traditional risks for DM, such as higher BMI or waist circumference, are associated with increased risk of incident DM among PWH with pre-DM. The association between lower CD4 + and progression to DM suggests a role for advanced immunodeficiency and inflammation. Further investigation of interventions aimed at preventing DM among PWH with pre-DM is needed. Optimizing prevention and treatment for DM may be an intervenable opportunity to improve long-term outcomes for PWH.

:The ability of virally suppressive antiretroviral therapy use to extend the life span of people with HIV (PWH) implies that the age of PWH will also increase. Among PWH, extended survival comes at a cost of earlier onset and increased rates of aging-associated comorbidities and geriatric syndromes, with persistent inflammation and immune dysregulation consequent to chronic HIV infection and to antiretroviral therapy use contributing to an overall decrease in health span. The geroscience hypothesis proposes that the root causes of most aging-related chronic diseases and conditions is the aging process itself. Hence, therapeutically targeting fundamental aging processes could have a greater impact on alleviating or delaying aging-associated comorbidities than addressing each disease individually. Extending the geroscience hypothesis to PWH, we speculate that targeting basic mechanisms of aging will improve overall health with age. Clinical features and pathophysiologic mechanisms of chronic diseases in PWH qualitatively resemble those seen in older adults without HIV. Therefore, drugs that target any of the pillars of aging, including metformin, rapamycin, and nicotinamide adenine dinucleotide precursors, may also slow the rate of onset of age-associated comorbidities and geriatric syndromes in PWH. Drugs that selectively induce apoptosis of senescent cells, termed senolytics, may also improve health span among PWH. Preliminary evidence suggests that senescent cell burden is increased in PWH, implying that senescent cells are an excellent therapeutic target for extending health span. Recently initiated clinical trials evaluating senolytics in age-related diseases offer insights into the design and potential implementation of similar trials for PWH.

The two-drug regimen dolutegravir plus lamivudine demonstrated durable efficacy for up to 3 years in phase III studies and a high barrier to resistance in treatment-naive and virologically suppressed people with HIV (PWH). This systematic literature review summarizes real-world evidence evaluating effectiveness and safety of dolutegravir plus lamivudine. We searched Ovid MEDLINE®, Embase®, PubMed, Cochrane library, and relevant international conference proceedings from 2013 to 2020. Qualitative synthesis of virologic suppression at Week 48, treatment-emergent resistance, discontinuation rates, and comorbidities was undertaken, with no statistical analyses conducted. Linked publications and potential for duplication in reporting of outcomes for cohorts and populations were identified, and the publication reporting the highest number of PWH receiving dolutegravir plus lamivudine was included in the analysis. Thirty-four studies reporting on cohorts of PWH not suspected to be linked or to include duplicate data receiving dolutegravir plus lamivudine were identified (N = 5017). Of 3744 virologically suppressed PWH who switched to dolutegravir plus lamivudine, 603 (16%) reported history of virologic failure. Nineteen studies included effectiveness data (n = 3558), four of which included data from treatment-naive PWH (n = 69). In studies with > 100 PWH, high rates of virologic suppression (Week 48, 97–100%) were maintained with dolutegravir plus lamivudine, with low rates of virologic failure (0–3.3 per 100 person-years of follow-up); one instance of emergent integrase strand transfer inhibitor resistance was reported in a complex treatment-experienced individual. Rates of discontinuation due to adverse events were low and consistent with previously observed trial data. Dolutegravir plus lamivudine minimally impacted renal function and had minimal impact on or improved lipid profiles and bone mineral density. This systematic review demonstrates that effectiveness and safety of dolutegravir plus lamivudine in clinical practice support data from randomized controlled trials with regard to high rates of virologic response, low rates of discontinuation, and a high barrier to resistance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00522-7.

Immediate and Long-Term Effects of a Computerized Cognitive Rehabilitation Therapy on Cognitive Function in People Living with HIV in Iran: A Single-Blind Two-Arm Parallel Randomized Controlled Trial.

Cognitive impairments have been endemic to the HIV epidemic since its beginning and persist to this day. These impairments are attributed to HIV-induced neuroinflammation, the long-term effects of combination antiretroviral therapy, lifestyle factors (e.g., sedentary behavior, substance use), neuro-comorbidities (e.g., depression), age-associated comorbidities (e.g., heart disease, hypertension), and others causes. Normal aging and lifestyle also contribute to the development of cognitive impairment. Regardless of the etiology, such cognitive impairments interfere with HIV care (e.g., medication adherence) and everyday functioning (e.g., driving safely, financial management). With more than half of people with HIV (PWH) 50 years and older, and ~45% of all PWH meeting the criteria for HIV-Associated Neurocognitive Disorder (HAND), those aging PWH are more vulnerable for developing cognitive impairment. This article provides an update to a social work model to identify and monitor PWH for cognitive impairment. Within this update, the state of the science on protecting brain health and cognitive reserve within the context of neuroHIV is also presented. From this, implications for practice and policy to promote successful cognitive functioning in older PWH are provided.

Some individuals with human immunodeficiency virus (HIV-1) have acquired multidrug-resistant (MDR) strains of HIV and/or are nonadherent to antiretroviral (ARV) medication. Injectable ARVs can provide salvage therapy for those with limited therapeutic options and may be preferred by some people with HIV (PWH). Real-world evidence may contribute to a more comprehensive understanding of the barriers to adherence and the utility of injectable ARVs in PWH. Currently, there is a lack of data on combined use of injectable ibalizumab (IBA) and lenacapavir (LEN) with optimized background regimen (OBR). A retrospective observational study examined medical charts from people with MDR HIV across 8 facilities in the United States. All PWH used a combination of both IBA + LEN ± OBR for at least 6 months. Viral loads and CD4+ counts were collected. A total of 21 PWH were included. Four-class resistance at baseline was reported in 38.1% of PWH. Within 12 to 24 weeks of combined IBA + LEN treatment, a median reduction of -2710 copies/mL HIV RNA was observed. Median increase to CD4+ count was 67.5 cells/mm3 within 4 to 44 weeks of treatment initiation. Few intolerances required changes to treatment. Therapy with IBA + LEN continued for an average of 30 months and 20 months, respectively. In this small group of individuals with MDR HIV who were heavily treatment-experienced and/or faced adherence challenges, the use of IBA + LEN ± OBR was well tolerated and led to clinically significant reductions in viral loads and improvements in CD4+ counts.

Although guidelines for COVID-19 additional vaccination strategies generally prioritise people with advanced HIV infection, recommendations vary globally, with some countries recommending an annual vaccination for all people with HIV (PWH), while others restrict this to PWH with a CD4+ T-cell count < 200 cells per µL. We conducted a prospective cohort study in 448 adult PWH. The primary outcome was the SARS-CoV-2 spike (S1)-specific IgG antibody level at 1, 6, 12, 18, and 24 months after completing a primary COVID-19 vaccination series (two doses of BNT162b2, mRNA-1273, or ChAdOx1-S, or one dose of Ad26.COV2.S). We compared the antibody kinetics over two years between PWH with a baseline CD4+ T-cell count < 200 cells per µL (n = 16) vs. ≥ 200 cells per µL (n = 432) with a mixed-effects model. Secondary outcomes included variables associated with the kinetics of S1-specific antibody levels and the incidence of breakthrough infections. The median most recent CD4+ T-cell count prior to primary vaccination was 140 (IQR 80-165) in the < 200 cells per µL group, and 688 (IQR 520-899) in the ≥ 200 cells per µL group at the time of primary vaccination. S1-specific antibodies were lower in PWH with a CD4+ T-cell count < 200 vs. ≥ 200 cells per µL during the two-year follow-up, with predicted S1-specific antibody levels of 514 (95% CI 456-578) vs. 2758 (95% CI 1488-5110) BAU per mL at 12 months (p < 0.001) and 839 (95% CI 732-959) vs. 3505 (95% CI 1712-7175) BAU per mL at 24 months (p < 0.001). The overall incidence of SARS-CoV-2 infections was 55% and comparable between groups. A CD4+ T-cell count < 200 cells per µL, higher age, and a vector-based primary vaccination series were negatively associated with S1-specific antibody levels over time. Long-term humoral responses were lower in PWH with a CD4+ T-cell count < 200 cells per µL compared to those with a CD4+ T-cell count ≥ 200 cells per µL. National COVID-19 vaccine guidelines recommending booster vaccines for all PWH, should therefore specifically emphasise the need for booster vaccines in those with a CD4+ T-cell count < 200 cells per µL. Trial registration: The trial was registered on the International Clinical Trials Platform (registration number: EUCTR2021-001054-57-N).

<h3>Objective:</h3> To identify and characterize neurodegenerative biotypes in people with HIV (PWH). <h3>Background:</h3> PWH may develop brain atrophy and neurocognitive dysfunction despite suppressive antiretroviral therapy. Distinguishing biotypes within this population is critical since they may represent unique underlying pathophysiological mechanisms and require different therapeutic approaches. <h3>Design/Methods:</h3> Participants in a longitudinal natural history study of a large, well-characterized, diverse cohort of PWH and matched controls underwent deep phenotyping including MRI and neuropsychological testing. Subcortical gray matter (SGM) and ventricular volumetrics were derived from FreeSurfer, then transformed into percentiles adjusted for age, sex, skull size, and MRI scanner. Correlation coefficients between percentile and clinical variables were calculated. Logistic regression assessed effects of continuous clinical variables on binary percentiles. <h3>Results:</h3> Our cohort included 209 PWH (159 male, 50 female) and 64 controls (34 male, 30 female). Subsets with the worst 20^th percentile of SGM atrophy (n=51) or ventricular enlargement (n=77) were identified. In PWH with SGM atrophy (n=43), analyses controlled for age, sex, and IQ showed positive associations with overall T-score (r=0.41, p=0.008); executive (r=0.43, p=0.004), learning (r=0.37, p=0.015), memory (r=0.38, p=0.014), and motor (r=0.36, p=0.021) domains; and global deficit score (GDS) (r=−0.37, p=0.015). Interestingly, SGM percentile also negatively correlated with total cholesterol (r=−0.44, p=0.014). Ventricular enlargement was associated with lower overall T-score in both HIV+ males (OR=0.92, CI=0.87–0.98, p=0.011) and HIV+ females (OR=0.89, CI=0.80–0.98, p=0.032). In HIV+ males, ventricular enlargement was associated with reduced verbal (OR=0.94, CI=0.89–0.98, p=0.010), speed of information processing (OR=0.96, CI=0.91–1.00, p=0.037), and motor (OR=0.94, CI=0.89–0.98, p=0.004) performance. In HIV+ females, it was associated with increased GDS (OR=8.20, CI=1.43–81.56, p=0.042) and systolic blood pressure (OR=1.04, CI=1.00–1.09, p=0.038). <h3>Conclusions:</h3> PWH with neurodegeneration can be grouped into SGM atrophy or ventricular enlargement biotypes. These subsets associate with distinct neurocognitive deficits and clinical risk factors, suggesting disparate underlying pathophysiological mechanisms. <b>Disclosure:</b> Ms. Dietrich has nothing to disclose. Ms. McMahan has nothing to disclose. Tianxia Wu has nothing to disclose. Mr. Bhagavatheeshwaran has received research support from National Institutes of Health. Dr. Reich has received research support from NIH. The institution of Dr. Reich has received research support from Vertex Pharmaceuticals. The institution of Dr. Reich has received research support from Adelson Medical Research Foundation. The institution of Dr. Reich has received research support from Myelin Repair Foundation. The institution of Dr. Reich has received research support from Sanofi-Genzyme. The institution of Dr. Reich has received research support from Abata Therapeutics. The institution of Dr. Reich has received research support from National Multiple Sclerosis Society. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with PeerView. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with AcademicCME. Dr. Reich has a non-compensated relationship as a Advisor with Sanofi-Genzyme that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Board of Directors with ACTRIMS that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Abata Therapeutics that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Roche that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with American Brain Foundation that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with University of Basel RC2NB that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Multiple Sclerosis Society of Canada that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Tuscan Doctorate in Neuroscience that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Editorial Board with Multiple Sclerosis Journal that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Glaxo-Smith-Kline that is relevant to AAN interests or activities. Dr. Snow has received research support from NIH/NIMH. The institution of Anuradha Ganesan has received research support from NIAID. Dr. Berjohn has received personal compensation in the range of $100,000-$499,999 for serving as a Active Duty Physician salary with US Navy. Brian K. Agan has received personal compensation for serving as an employee of Henry M. Jackson Foundation for the Advancement of Military Medicine. Dr. Nath has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Nath has received research support from National Institutes of Health. The institution of Dr. Nath has received research support from ALS Association. Dr. Smith has nothing to disclose.

Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables. To examine LA-ART in a population of PWH that includes those with viremia. Observational cohort study. Urban academic safety-net HIV clinic. Publicly insured adults living with HIV with and without viral suppression, high rates of unstable housing, mental illness, and substance use. Demonstration project of long-acting injectable CAB-RPV. Descriptive statistics summarizing cohort outcomes to date, based on pharmacy team logs and electronic medical record data. Between June 2021 and November 2022, 133 PWH at the Ward 86 HIV Clinic were started on LA-ART, 76 of whom had virologic suppression while using oral ART and 57 of whom had viremia. The median age was 46 years (IQR, 25 to 68 years); 117 (88%) were cisgender men, 83 (62%) had non-White race, 56 (42%) were experiencing unstable housing or homelessness, and 45 (34%) had substance use. Among those with virologic suppression, 100% (95% CI, 94% to 100%) maintained suppression. Among PWH with viremia, at a median of 33 days, 54 of 57 had viral suppression, 1 showed the expected 2-log10 reduction in HIV RNA level, and 2 experienced early virologic failure. Overall, 97.5% (CI, 89.1% to 99.8%) were projected to achieve virologic suppression by a median of 33 weeks. The current virologic failure rate of 1.5% in the cohort is similar to that across registrational clinical trials at 48 weeks. Single-site study. This project demonstrates the ability of LA-ART to achieve virologic suppression among PWH, including those with viremia and challenges to adherence. Further data on the ability of LA-ART to achieve viral suppression in people with barriers to adherence are needed. National Institutes of Health, City and County of San Francisco, and Health Resources and Services Administration.

Chapter 11 - Clinical Trial Design in Immuno-Oncology

Assessing the adoption, acceptability and fidelity of the alcohol use disorders test for alcohol use disorders screening in HIV clinics in Malawi.

Background Despite the availability and efficacy of two-drug regimens (2DR) for HIV treatment, three-drug regimens (3DR) are mostly used by people with HIV (PWH). We evaluated virologic outcomes of initiating or switching to a 2DR vs 3DR among PWH in Washington, DC. Adjusted Cox Proportional Hazard Regression Model for Virologic Non-Suppression (viral load &amp;gt; 200 copies/mL) among PWH by Two- and Three-Drug Regimens in the DC Cohort, 2019-2023 Methods We included DC Cohort treatment-experienced participants initiating or switching to a 2DR or 3DR on or after July 2019 with ≥2 years of follow-up. Descriptive statistics for demographic and clinical factors at regimen initiation, including HIV viral load (VL) and CD4 count (cells/µL), were stratified by 2DR or 3DR. Multivariable Cox proportional hazard modeling was performed among participants virally suppressed (VS; VL&amp;lt; 200 copies/mL) at regimen initiation to assess the time to non-virologic suppression (non-VS) using adjusted hazard ratios (aHR) and 95% CI adjusting for demographics, HIV risk, and regimen. Among participants who were not VS at the time of regimen initiation, we conducted a sub-analysis of the time to VS. Results We analyzed 1782 participants (72.8% 3DR, 28.2% 2DR (161 switched from a 3DR); age 54.3 years (IQR 43.8-61.3), 68.8% male; 78.1% Black) with a median CD4 621 (IQR 409-868) at regimen initiation. Participants on 2DR were older (56.4 vs 53.6 years; p&amp;lt; 0.001) and had higher VS rates (93.8% vs 88.2%; p&amp;lt; 0.001) at regimen initiation and shorter regimen times (3.2 vs 3.8 years; p&amp;lt; 0.001) compared to 3DR. 2DR participants were more likely to have public vs private insurance and receive hospital vs community-based care. The risk of non-VS was higher among those with CD4 &amp;lt; 200 and 200-500 (aHR 1.5(1.0-2.1) and aHR 2.0(1.1-3.6), respectively) compared to those with CD4 &amp;gt;500. Those with public insurance were also more likely to experience non-VS (aHR 1.5; p&amp;lt; 0.05). While regimen type was not a significant predictor of non-VS, there was an elevated risk among those on 3DR (aHR 1.2) compared to 2DR [Figure]. Among those non-VS at regimen initiation (n=146), the median time to VS was similar among PWH on 2DR (14.1 months) and 3DR (13.8 months; p=0.76). Conclusion Non-VS PWH have similar time to VS regardless of whether they receive 2DR or 3DR, suggesting similar efficacy of 2DR and 3DR in these populations. Patients with CD4 &amp;lt; 500 had higher risk of non-VS on 2DR, supporting the usefulness of the CD4 criteria factor when selecting 2DR vs 3DR. Disclosures All Authors: No reported disclosures