Higher Baseline CD4 Research Articles

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/μL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/μL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Immunological and virological response to fostemsavir in routine US clinical care: An OPERA cohort study.

Fostemsavir is a novel attachment inhibitor used with other antiretrovirals in heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. Real-world immunological and virological responses were assessed in individuals starting fostemsavir in the OPERA cohort. Among adults with HIV-1 starting fostemsavir between 2 July 2020 and 1 September 2022, 6-month and 12-month changes in CD4 T-cell count and CD4%, and maintenance/achievement of viral load (VL) <50 copies/mL were described and stratified by baseline VL (suppressed: <50 copies/mL; viraemic: ≥50 copies/mL) and CD4 count (high: ≥350 cells/μL; low: <350 cells/μL). Of 182 individuals starting fostemsavir, 64% were viraemic (34% low CD4, 30% high CD4) and 36% were suppressed (16% low CD4, 20% high CD4). The suppressed/low CD4 group had the largest median increases in CD4 count (6-month: 30 cells/μL [interquartile range {IQR} 9-66], 12-month: 66 cells/μL [IQR 17-125]), and CD4% (6-month: 1.0% [IQR -0.3-2.8], 12-month: 1.9% [IQR 1.3-3.9]). Regardless of baseline VL, those with a high baseline CD4 count experienced a greater variability in immunological response than those with low CD4 counts (12-month standard deviation range 172-231 cells/μL vs. 69-90 cells/μL). VL <50 copies/mL was maintained in most suppressed individuals; nearly half of the viraemic/high CD4 group and a third of the viraemic/low CD4 group achieved a VL <50 copies/mL at either timepoint. After 6 or 12 months of fostemsavir use, virological response was low in viraemic individuals, although most suppressed individuals did maintain suppression. While immunological response varied across individuals, virologically suppressed HTE individuals with low CD4 counts may benefit from immunological improvements with fostemsavir.

Investigating the Relationship between Medication Adherence Behaviors and the Achievement of Sustained Viral Load Suppression among People Living with HIV (PLHIV) on Antiretroviral Therapy (ART) in Akwa Ibom State, from 2018 - 2022

Background: Nigeria is still endemic for Human Immuno-Deficiency Virus (HIV), and currently among the top five countries with the highest burdens of HIV infection. For a successful HIV program, there should be good access to antiretroviral therapy (ART) and record of viral load suppression (VLS). This study aimed at investigating the relationship between medication adherence behavior (MAB) and sustained VLS among people living with HIV (PLHIV) receiving ART in Akwa Ibom State. Methods: This was a retrospective cohort study of the medical records of 1,763 PLHIV receiving ART services from January 2018 to December 2022, in selected ten health facilities in Akwa Ibom State. Relevant demographic, clinical, immunological, viral load (VL) information were obtained from the patients’ medical records and databases. The proportion of VLS and associated variables were then analyzed. Results: Out of the 2,550 PLHIV whose medical records were accessed, data for 1,763 PLHIV was accepted for analysis. A total of 795 (45.1%) male and 968 (54.9%) female participated in the study, with a mean age of 38.4 ± 5 years. While 23.8% (n = 420) have unsuppressed VL of &gt;1,000 copies/mL; 76.2% (n = 1,343) of participants achieved VLS of &lt;1,000 copies/mL. 90.4% (n = 1,213) of the virally suppressed participants recorded moderate to high medication adherence levels (X2 = 94.977, df = 2, p-value = 2.2 x 10-16). CD4 counts and HAART regimen have significant impact on VLS (p &lt; 0.05), while pregnancy status, TB Infection, duration on HAART, and WHO disease stage do not have significant effects on VLS (p &gt; 0.05). Conclusion: There was a strong evidence to reject the null hypothesis, which states that there is no positive association between MAB and sustained VLS among PLHIV on ART (p &lt; 0.05). The VLS rate in this study indicates a good HIV epidemic control. Good medication adherence level, high baseline CD4 count, and being on first line HAART regimen were strongly associated with VLS.

Impact of Latent M. tuberculosis Infection Treatment on Time to CD4/CD8 Recovery in Acute, Recent, and Chronic HIV Infection.

In people living with HIV, active and latent tuberculosis (TB) coinfections are associated with immune activation that correlate with HIV progression and mortality. We investigated the effect of initiating antiretroviral therapy (ART) during acute (AHI), recent (RHI), or chronic HIV infection (CHI) on CD4/CD8 ratio normalization and associated factors, the impact of latent TB infection treatment, and prior/concomitant TB diagnosis at the time of ART initiation. We included sex with men and transgender women individuals initiating ART with AHI, RHI and CHI between 2013 and 2019, from a prospective cohort in Brazil. We compared time from ART initiation to the first normal CD4/CD8 ratio (CD4/CD8 ≥1) using Kaplan-Meier curves and multivariable Cox proportional hazards models. Sociodemographic and clinical variables were explored. Variables with P -values <0.20 in univariable analyses were included in multivariable analyses. Five hundred fifty participants were included, 11.8% classified as AHI and 6.4% as RHI, 46.7% with CHI-CD4 cell counts ≥350 cells/mm 3 and 35.1% with CHI-CD4 cell counts <350 cells/mm 3 . Time to normalization was shortest among AHI patients, followed by RHI and CHI individuals with higher baseline CD4. In the multivariable model, AHI was associated with a six-fold increased likelihood of achieving a CD4/CD8 ratio ≥1 (hazard ratio [HR]: 6.03; 95% confidence interval [CI]: 3.70 to 9.82; P < 0.001), RHI with HR: 4.47 (95% CI: 2.57 to 7.76; P < 0.001), and CHI CD4 ≥350 cells/mm 3 with HR: 1.87 (95% CI: 1.24 to 2.84; P = 0.003). Latent TB infection treatment was significantly associated with a higher likelihood of the outcome (HR: 1.79; 95% CI: 1.22 to 2.62; P = 0.003). Previous history or concomitant active TB at ART initiation was associated with a lower likelihood of the outcome (HR: 0.41; 95% CI: 0.16 to 1.02; P = 0.054). Initiating ART early during AHI may offer an opportunity to mitigate immune damage. Efforts to implement HIV diagnosis and ART initiation during AHI are critical to amplify ART benefits.

Spatial distribution of tumor-infiltrating T cells indicated immune response status under chemoradiotherapy plus PD-1 blockade in esophageal cancer.

The spatial distribution of tumor-infiltrating T cells and its dynamics during chemoradiotherapy combined with PD-1 blockade is little known in esophageal squamous cell carcinoma (ESCC). We applied the multiplex immunofluorescence method to identify T cells (CD4+, CD8+ T cells, and their PD-1- or PD-1+ subsets) and myeloid-derived cells (CD11c+ dendritic cells, CD68+ macrophages, and their PD-L1+ subpopulations) in paired tumor biopsies (n = 36) collected at baseline and during combination (40 Gy of radiation) from a phase Ib trial (NCT03671265) of ESCC patients treated with first-line chemoradiotherapy plus anti-PD-1 antibody camrelizumab. We used the FoundationOne CDx assay to evaluate tumor mutational burden (TMB) in baseline tumor biopsies (n = 14). We dynamically assessed the nearest distance and proximity of T-cell subsets to tumor cells under combination and estimated the association between T-cell spatial distribution and combination outcome, myeloid-derived subsets, TMB, and patient baseline characteristics. We found that the tumor compartment had lower T-cell subsets than the stromal compartment but maintained a comparable level under combination. Both before and under combination, PD-1- T cells were located closer than PD-1+ T cells to tumor cells; T cells, dendritic cells, and macrophages showed the highest accumulation in the 5-10-μm distance. Higher CD4+ T cells in the tumor compartment and a shorter nearest distance of T-cell subsets at baseline predicted poor OS. Higher baseline CD4+ T cells, dendritic cells, and macrophages were associated with worse OS in less than 10-μm distance to tumor cells, but related with better OS in the farther distance. Higher on-treatment PD-1-positive-expressed CD4+ and CD8+ T cells within the 100-μm distance to tumor cells predicted longer OS. T cells, dendritic cells, and macrophages showed a positive spatial correlation. Both high TMB and smoking history were associated with a closer location of T cells to tumor cells at baseline. We firstly illustrated the T-cell spatial distribution in ESCC. Combining chemoradiotherapy with PD-1 blockade could improve the antitumor immune microenvironment, which benefits the treatment outcome. Further understanding the precision spatiality of tumor-infiltrating T cells would provide new evidence for the tumor immune microenvironment and for the combination treatment with immunotherapy.

Incomplete Antiretroviral Therapy Adherence Is Associated with Lower CD4-CD8 Ratio in Virally Suppressed Patients with HIV Infection in Mexico.

Suboptimal adherence to antiretroviral therapy (ART) in people with HIV, even during sustained viral suppression, is associated with persistent inflammation, immune activation, and coagulopathy. Persistently low CD4-CD8 Ratio has been also associated with residual inflammation, is a good predictor of increased risk of death and more widely available than inflammatory biomarkers. We tested the hypothesis that the CD4-CD8 Ratio is associated with ART adherence during periods of complete viral suppression. We used the Medication Possession Ratio based in pharmacy registries as measure of adherence and time-varying, routine care CD4 and CD8 measurements as outcome. We used a linear mixed model for longitudinal data, including fixed effects for sex, age, education, date of ART initiation, AIDS-related conditions, and baseline CD4 to model the outcome. In 988 adults with a median follow-up of 4.13 years, higher ART adherence was independently associated with a modest increase in CD4-CD8. For each increasing percentage point in adherence, the CD4-CD8 Ratio increased 0.000857 (95% confidence interval [CI] -0.000494 to 0.002209, p = .213731) in the first year after achieving viral suppression; 0.001057 (95% CI 0.000262-0.001853, p = .009160) in years 1 to 3; 0.000323 (95% CI -0.000448 to 0.001095, p = .411441) in years 3 to 5; and 0.000850 (95% CI 0.000272-0.001429, p = .003946) 5-10 years after achieving viral suppression. The magnitude of the effect of adherence over CD4-CD8 Ratios varied over time and by baseline CD4 count, with increasing adherence having a larger effect early after ART initiation in people with higher baseline CD4 (>500 cells/μL) and in later years in people with lower baseline CD4 count (≥200 cells/μL). Our findings expand on previous evidence suggesting that the benefits of optimal adherence to modern ART regimens goes beyond maintaining viral suppression. These results highlight the importance of including objective measurements of adherence as part of routine care, even in patients with complete HIV suppression over long-term follow-up.

Advances in Research on COVID-19 Vaccination for People Living with HIV.

Advances in Research on COVID-19 Vaccination for People Living with HIV.

CD4+ cell count recovery after initiation of antiretroviral therapy in HIV-infected Ethiopian adults.

CD4+ cell count recovery after effective antiretroviral therapy (ART) is an important determinant of both AIDS and non-AIDS morbidity and mortality. Data on CD4+ cell count recovery after initiation of ART are still limited in Sub-Saharan Africa. The aim of this study was to assess CD4+ cell count recovery among HIV-infected adults initiating ART in an Ethiopian setting. A retrospective cohort study of HIV-infected adults initiating ART between September 2008 and June 2019 was carried out. CD4+ cell count recovery was defined as an increase in CD4+ cell count of >100 cells/mm3 from baseline or achievement of a CD4+ cell count >500 cells/mm3 at 12 months after ART initiation. Factors associated with CD4+ cell count recovery were evaluated using logistic regression analysis. Of the 566 patients included in this study, the median baseline CD4+ cell count was 264 cells/mm3 (IQR: 192-500). At 12 months after ART initiation, the median CD4+ cell count increased to 472 cells/mm3, and the proportion of patients with CD4+ cell count < 200 cells/mm3 declined from 28.3 to 15.0%. A total of 58.0% of patients had an increase in CD4+ cell count of >100 cells/mm3 from baseline and 48.6% achieved a CD4+ cell count >500 cells/mm3 at 12 months. Among patients with CD4+ cell counts < 200, 200-350 and >350 cells/mm3 at baseline, respectively, 30%, 43.9% and 61.7% achieved a CD4+ cell count >500 cells/mm3 at 12 months. In multivariable analysis, poor CD4+ cell count recovery (an increase of ≤100 cells/mm3 from baseline) was associated with older age, male sex, higher baseline CD4+ cell count and zidovudine-containing initial regimen. Factors associated with poor CD4+ cell count recovery to reach the level >500 cells/mm3 included older age, male sex and lower baseline CD4+ cell count. CD4+ cell count failed to recover in a substantial proportion of adults initiating ART in this resource-limited setting. Older age, male sex and baseline CD4+ cell count are the dominant factors for poor CD4+ cell count recovery. Novel therapeutic approaches are needed focusing on high risk patients to maximize CD4+ cell count recovery and improve outcomes during therapy.

Immunogenicity of an inactivated SARS-CoV-2 vaccine in people living with HIV-1: a non-randomized cohort study.

BackgroundInactivated COVID-19 vaccines are safe and effective in the general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH).Methods42 HIV-1 infected individuals who were stable on combination antiretroviral therapy (cART) and 28 healthy individuals were enrolled in this open-label two-arm non-randomized study at Hubei Provincial Center for Disease Control and Prevention, China. Two doses of an inactivated COVID-19 vaccine (BBIBP-CorV) were given on April 22, 2021 and May 25, 2021, respectively. The reactogenicity of the vaccine were evaluated by observing clinical adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and surrogate neutralization assays. Cell-mediated immune responses and vaccine induced T cell activation were measured by flow cytometry.FindingsAll the HIV-1 infected participants had a CD4+ T cell count >200 cells/μL both at baseline (659·0 ± 221·9 cells/μL) and 4 weeks after vaccination (476·9 ± 150·8 cells/μL). No solicited adverse reaction was observed among all participants. Similar binding antibody, neutralizing antibody and S protein specific T cell responses were elicited in PLWH and healthy individuals. PLWH with low baseline CD4+/CD8+ T cell ratios (<0·6) generated lower antibody responses after vaccination than PLWH with medium (0·6∼1·0) or high (≥1·0) baseline CD4+/CD8+ T cell ratios (P<0·01). The CD3+, CD4+ and CD8+ T cell counts of PLWH decreased significantly after vaccination (P<0·0001), but it did not lead to any adverse clinical manifestation. Moreover, we found that the general HIV-1 viral load among the PLWH cohort decreased significantly after vaccination (P=0·0192). The alteration of HIV-1 viral load was not significantly associated with the vaccine induced CD4+ T cell activation (P>0·2).InterpretationOur data demonstrated that the inactivated SARS-CoV-2 vaccine was safe, immunogenic in PLWH who are stable on cART with suppressed viral load and CD4+ T cell count > 200 cells/μL. However, the persistence of the vaccine-induced immunities in PLWH need to be further investigated.

Immune Reconstitution following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with or without Pembrolizumab Maintenance Therapy in Patients with Lymphoma

Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1+ T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ terminal effector memory cell count (defined as CD3+CD4+CD45RA+CD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P=.003). As continuous variables, lower absolute levels of NK cells (P=.009), PD-1+ CD4+ T cells (P=.005), and PD-1+ CD8+ T cells (P=.005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Viral suppression among HIV-positive patients on antiretroviral therapy in northwestern Nigeria: an eleven-year review of tertiary care centre records, January 2009\u2013December 2019

BackgroundHuman Immuno-Deficiency Virus (HIV) remains one of the world’s significant public health challenges. Viral suppression is the key indicator for treatment success in People living with HIV (PLHIV). We determined the level of viral suppression, and its associated factors among PLHIV attending Federal Medical Centre Katsina (FMC Katsina), Nigeria.MethodsThis retrospective descriptive cross-sectional study was conducted on 913 HIV positive adults enrolled in care between January 2009 and December 2019. Information on socio-demographics, clinical, immunological, Viral load (VL), and other relevant parameters were extracted from the patients’ care records. The primary outcome was the proportion of patients that achieved viral suppression. We also analyzed variables that were associated with VL suppression.ResultsOf 913, records of 831 (91.0%) registered patients were analyzed. During the period, 751 (90.4%) achieved viral suppression, 427 (51.4%) had CD4 counts ≥ 500 and 477 (57.4%) were on HAART for ≥ 5 years. Majority, 793 (95.4%) were on first-line HAART regimen (Tenofovir-Lamivudine-Dolutegravir or Abacavir-Lamivudine-Dolutegravir), and 809 (97.4%) in the non-advanced stage (WHO stages 1 and 2). The median (interquartile range) of viral load was 20 (20–40) vs 19,989 (3311–110,340) cp/ml in virally suppressed, and unsuppressed respectively. Factors associated with viral suppression included being unemployed (Adjusted OR [AOR] 4.9, 95% CI 2.771, 8.539), educated (AOR 4.2, 95% CI 1.098, 16.223), having a baseline CD4 count ≥ 500 cells/µl (AOR 2.7, 95% CI 1.588, 4.625), and being on first line HAART regimen [AOR 7.0, 95% CI 3.220, 15.648].ConclusionsOur study demonstrated a good viral suppression among PLHIV on HAART. Variables associated with viral suppression included unemployment, formal education, high baseline CD4 count, and first line HAART regimen.

Influence of HLA-B*5701 on 20 year survival rate among patients living with HIV.

BackgroundThe life expectancy of people living with HIV (PLWH) remains shorter than that of the general population, despite significant improvement in the recent years. Mortality in HIV-infected individuals may be associated with a higher viral load at of diagnosis, a lower CD4 count, or clinical variables such as sex or route of transmission. This article investigated the role of the HLA-B*5701 varian on mortality among PLWH.MethodsMaterial for the analysis consist of the data of 2,393 patients for whom the HLA-B*57 variant was known. Those patients were followed under the care of the Infectious Diseases Hospital in Warsaw (n = 1555) and the Clinic of Acquired Immunodeficiency of the Pomeranian Medical University in Szczecin (n = 838). Factors such as age, gender, date of HIV diagnosis, route of transmission, date of death, baseline HIV viral load and baseline CD4 counts, were collected, and end-point cross-sectional analyses were marked at 60, 120, 180 and 240 month of observation.ResultsHLA-B*5701 allele was found in 133 (5.5%) analyzed cases. Median age was notably higher for HLA-B*5701 positive patients [32.7 (28.3–41.3) vs. 31.6 (26.8–38.3)years p = 0.02]. HLA-B*5701 was associated with lower baseline viral load [4.21 (3.5–4.8) vs. 4.79 (4.2–5.3)log copies/ml p<0.001] and higher CD4count [448 (294.5–662) vs. 352 (176–514) cells/μl p<0.001]. There were no association between HLA-B*5701 and survival for any given end-point. Higher mortality was associated to male gender, intravenous drug users, lower CD4 count at baseline and higher baseline viral load.ConclusionsIn our study, the presence of HLA-B*5701 allel was not associated with mortality rate of HIV infected patients, irrespective of being associated with both higher baseline CD4 + cell count and lower baseline HIV viral load.

Therapeutic prediction of HIV-1 DNA decay: a multicenter longitudinal cohort study

BackgroundFactors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions.MethodsTwo sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART.ResultsThe total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (< 100 copies/106 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P < 0.001] and higher baseline CD4+ T cell count (RR = 1.72, per 100 cells/μL, P < 0.001) were significantly associated with a low total HIV-1 DNA count at week 96. In an independent cohort of 117 patients, this model achieved a sensitivity of 75.00% and specificity of 69.52%.ConclusionsBaseline total HIV-1 DNA and CD4+ T cell count are two independent predictors of total HIV-1 DNA after treatment. The derived model based on these two baseline factors provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

Modelling treatment benefit for bexmarilimab (an anti-Clever-1 antibody and a novel macrophage checkpoint inhibitor) using phase I first-in-man trial data.

e14530 Background: Bexmarilimab, an investigational immunotherapeutic antibody targeting Clever-1, is currently investigated in phase I/II MATINS study (NCT03733990) for advanced solid tumors. Machine learning (ML) based models combining extensive data could be generated to predict treatment responses to this first-in-class macrophage checkpoint inhibitor. Methods: 58 baseline features from 30 patients included in the part 1 of phase I/II MATINS trial were included in ML modelling. Seven patients were classified as benefitting from the therapy by RECIST 1.1 (PR or SD response in target or non-target lesions). Initial feature selection was done using a combination of domain knowledge and removal of features with several missing values resulting in 20 clinically relevant features from 25 patients. The remaining data was standardized and feature selection using variance analysis (ANOVA) based on F-values between response and features was performed. With this approach, the number of features could be further reduced as the prediction performance increased until the most important features were included in the model. Several prediction models were trained, and prediction performance evaluated using leave-one-out cross-validation (LOOCV), with and without SMOTE oversampling of the positive class of the training data inside each LOOCV fold. In LOOCV the prediction model was trained 25 times. Stacked meta classifier with SMOTE oversampling combining three classifiers: elastic-net logistic regression, random forest and extreme gradient boosting was chosen as the best performing prediction model. Results: Seven baseline features were associated with bexmarilimab treatment benefit. Increasing bexmarilimab dose and high tumor FoxP3 cells showed positive benefit. On contrary, high baseline blood neutrophils, CD4, T-cells, B-cells, and CXCL10 indicated negative relationship to the treatment benefit. The ML model trained with these seven features performed well in LOOCV as 6/7 benefitting and 16/18 non-benefitting were classified correctly, and all considered classification performance metrics were good. In feature importance analysis, low baseline CXCL10 and neutrophils were characterized as the most important predictors for treatment benefit with values of 0.19 and 0.16. Conclusions: This study highlights possibility of using ML models in predicting treatment benefit for novel cancer drugs such as bexmarilimab and boost the clinical development. These findings are in line of expected immune activation of bexmarilimab treatment. The generated ML models should be further validated in a larger patient cohort. Clinical trial information: NCT03733990.

Effect of chemoradiotherapy on the proportion of circulating lymphocyte subsets in patients with limited-stage small cell lung cancer.

Chemoradiotherapy (CRT) is the standard treatment for limited-stage small cell lung cancer (LS-SCLC), which can exert anti-tumor effects by regulating immune cells. Different immune cell subsets are associated with a specific sensitivity to CRT. The purpose of this study was to characterize the proportion or composition of peripherallymphocytes in patients with LS-SCLC before and after CRT, and evaluate their prognostic value. A total of 98 patients with LS-SCLC were enrolled. The expression of CD3, CD4, CD8, CD45RA, CD45RO, CD38, CD56, and CD19 on the surface of peripheral blood cells was detected by flow cytometry and retrospectively analyzed. The relationship between the proportion of lymphocyte subsets, progression-free survival (PFS), and overall survival (OS) was evaluated using a log-rank test and Cox regression model. The median PFS was 12.3months and the median OS was 21.7months. Compared with the pre-treatment specimens, post-treatment lymphocytes had increased proportions of CD3+, CD3+CD8+, CD8+CD38+ T cells, and NKT cells, and a decreased proportion of CD3+CD4+ T cells, CD4+CD45RA+ T cells, B cells, NK cells, and CD4/CD8 ratio. Univariate and multivariate analyses showed that prophylactic cranial irradiation, high percentages of CD4+CD45RA+, CD8+CD38+ T cells after CRT independently predicted superior PFS. Male patients with a high baseline CD4+CD45RO+ T cell ratio predicted a poor OS. CRT induced changes in the proportion of circulating lymphocyte subsets in LS-SCLC, which is helpful for designing a regimen of immune drugs to be combined with CRT. The prognostic value of the proportion of lymphocytes aids in understanding the role of peripheral immune profiles in LS-SCLC.

Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection.

BackgroundThe predictors of weight gain remain unclear in people with acute and early HIV infection (AEH).MethodsEligible antiretroviral-naïve men diagnosed with AEH from January 1, 2000, to December 31, 2019, were enrolled in an observational cohort study at the University California, San Diego. The study used multivariable mixed-effect linear regression models to analyze differences in the rate of weight gain over time between participants receiving early vs deferred antiretroviral therapy (ART) treatment, low vs high baseline CD4 count and HIV RNA, and different classes of ART.ResultsA total of 463 participants were identified, with mean CD4 cell count of 507 cells/μL and log HIV RNA of 5.0 copies/mL at study entry. There was no difference in the rate of weight gain between participants who did and did not receive ART within 96 weeks of incident HIV infection. Neither a baseline CD4 count of <350 cells/μL nor a baseline HIV RNA of >100 000 copies/mL was a predictor of weight gain. Compared with persons taking non-nucleoside reverse transcriptase inhibitor–based regimens, those who received integrase strand transfer inhibitor (INSTI)–based regimens showed greater weight gain over time.ConclusionsNeither baseline CD4 count and HIV RNA nor early ART was associated with weight change in the first 96 weeks following incident HIV infection. Use of INSTI-based regimens represented a major driver of weight gain in men who initiated ART with relatively higher CD4 cell counts.

Increased CD4 : CD8 ratio normalization with implementation of current ART management guidelines.

To determine the time to CD4 : CD8 ratio normalization among Canadian adults living with HIV in the modern ART era. To identify characteristics associated with ratio normalization. Retrospective analysis of the Canadian Observational Cohort (CANOC), an interprovincial cohort of ART-naive adults living with HIV, recruited from 11 treatment centres across Canada. We studied participants initiating ART between 1 January 2011 and 31 December 2016 with baseline CD4 : CD8 ratio <1.0 and ≥2 follow-up measurements. Normalization was defined as two consecutive CD4 : CD8 ratios ≥1.0. Kaplan-Meier estimates and log-rank tests described time to normalization. Univariable and multivariable proportional hazards (PH) models identified factors associated with ratio normalization. Among 3218 participants, 909 (28%) normalized during a median 2.6 years of follow-up. Participants with higher baseline CD4+ T-cell count were more likely to achieve normalization; the probability of normalization by 5 years was 0.68 (95% CI 0.62-0.74) for those with baseline CD4+ T-cell count >500 cells/mm3 compared with 0.16 (95% CI 0.11-0.21) for those with ≤200 cells/mm3 (P < 0.0001). In a multivariable PH model, baseline CD4+ T-cell count was associated with a higher likelihood of achieving ratio normalization (adjusted HR = 1.5, 95% CI 1.5-1.6 per 100 cells/mm3, P < 0.0001). After adjusting for baseline characteristics, time-dependent ART class was not associated with ratio normalization. Early ART initiation, at higher baseline CD4+ T-cell counts, has the greatest impact on CD4 : CD8 ratio normalization. Our study supports current treatment guidelines recommending immediate ART start, with no difference in ratio normalization observed based on ART class used.

Immunovirological treatment outcomes after 2 years of antiretroviral therapy in children living with the human immune deficiency virus in Lagos Nigeria

Background/objective: The World Health Organization (WHO) recommends routine assessment of antiretroviral treatment outcomes to detect treatment failure early and prevent the development of drug resistance. The aim of this study was to describe treatment outcomes of antiretroviral therapy (ART) over 2 years in children living with the human immune deficiency virus enrolled in the paediatric HIV clinic at the Lagos UniversityTeaching Hospital (LUTH).Materials and methods: This was a retrospective study of antiretroviral treatment outcomes in 278 children receiving antiretroviral therapy at the paediatric HIV clinic of LUTH. Demographic, clinical and laboratory data were retrospectively collected from clinical records of pediatric patientswho received antiretroviral therapy for 2 years ( from November 2015 to December 2017) . Virological failure was defined as viral load &gt; 400 copies/ml and immunological failure was defined as a CD4 count &lt;100 cells/mm3 or CD4 % &lt;15% after receiving antiretroviral agents for 12 months. Data was analysed using graph pad prism version 5.0.Results: After 12 months on antiretroviral therapy (ART), 101 (36%) had virological failure while 14 (5%) and 36 (13%) failed immunologically [CD4 count &lt;100 cells/mn3 and CD4 &lt;15% respectively]. Virological blips were observed at 24 months in 6.1% of patients while immunovirological discordance occurred in 30% of patients (poor virological clearance despite good immunological recovery) . High baseline viral load (&gt;5000 copies/ml), poor adherence (&lt;95%) and low baseline CD4 counts (101-249 cells/mn3) were significantly associated with virological failure, while low baseline CD4 counts (&lt;350 cells/mn3) and poor adherence (&lt;95%) were significantly associated with immunologic failure.Conclusion: The treatment outcomes observed in this study are similar to those reported in earlier studies. At 1 and 2 years of antiretroviral therapy , there was immune restoration however 101 (36%) and 87 (31%) respectively had virological failure despite good adherence to therapy and good Immunological restoration. This calls for early initiation and switch to second and third line drugs .&#x0D; Key words: Human immunodeficiency virus (HIV), zidovudine, lamivudine, nevirapine, virological blips, immunovirological discordance , children, Nigeria.

Outcomes After Being Lost to Follow-up Differ for Pregnant and Postpartum Women When Compared With the General HIV Treatment Population in Rural South Africa.

Undetermined attrition prohibits full understanding of the coverage and effectiveness of HIV programs. Outcomes following loss to follow-up (LTFU) among antiretroviral therapy (ART) patients may differ according to their reasons for ART initiation. We compare the true outcomes of adult patients previously identified as LTFU by reason for ART initiation in 8 health facilities in north eastern South Africa. Adult HIV patient records were linked to health and demographic surveillance system (HDSS) data from 2014 to 2017. Outcomes of adults categorized as LTFU (>90 days late for the last scheduled clinic visit) were determined through clinic and routine tracing record reviews, consultation of HDSS data, and supplementary tracing. We calculated the proportion of patients per outcome category and performed competing risk survival analysis to estimate the cumulative incidence of death, transfer, migration, ART interruption, and re-engagement following LTFU. Of 895/1017 patients LTFU with an outcome ascertained, 120 (13.4%) had died, 225 (25.1%) re-engaged, 50 (5.6%) migrated out of the HDSS, 75 (8.4%) were alive and not on treatment, and 315 (35.1%) transferred their treatment. These outcomes varied by sex and pregnancy status at ART initiation. Mortality was less likely among pregnant women, patients with higher baseline CD4, and more likely among older patients. Patient survival and transfers to other facilities are considerably higher than those suggested in earlier studies. Outcomes differ for women who were pregnant or postpartum when initiating ART, with this population less likely to have died and more likely to have migrated.

High viral suppression and low attrition in healthy HIV-infected patients initiated on ART with CD4 above 500 cells/µL in a program setting in Uganda.

The World Health Organization recommends antiretroviral therapy (ART) for all HIV-infected patients at all CD4 counts. However, there are concerns that asymptomatic patients may have poorer viral suppression and high attrition. We sought to determine attrition and viral suppression among healthy HIV-infected patients initiated on ART in program settings. This cross-sectional study enrolled ART-experienced patients attending two PEPFAR-supported, high-volume clinics in Kampala, Uganda. Eligible patients were >18 years and had completed at least six months on ART. Participants were interviewed on socio-demographics, ART history and plasma viral load (VL) determined using Abbott Real-time. Predictors of viral suppression (<75 copies/ml) were determined using multivariate logistic regression. Overall, 267 participants were screened, 228 were eligible and 203 (89%) retained in care (visit within 90 days). Of the 203 participants, 115 (56.7%) were key-populations. Viral suppression was achieved in 173 patients (85%; 95% CI, 80.3%-90.1%). The factors associated with viral suppression were prior VL tests (AOR 6.98; p-value <0.001) and receiving care from a general clinic (AOR 5.41; p=0.009). Asymptomatic patients initiated on ART with high baseline CD4 counts, achieve high viral suppression with low risk of attrition. VL monitoring and clinic type are associated with viral suppression.