Treatment-naive Individuals Research Articles

Real-World Effectiveness of Dolutegravir/Lamivudine in People With HIV-1 in Test-and-Treat Settings or With High Baseline Viral Loads: TANDEM Study Subgroup Analyses.

Dolutegravir/lamivudine (DTG/3TC) was first approved by the US Food and Drug Administration in 2019 for the treatment of antiretroviral therapy (ART)-naive people with HIV-1 based on results from the pivotal GEMINI-1/GEMINI-2 trials. Around that time, immediate initiation of treatment upon diagnosis was recommended in the US Department of Health and Human Services guidelines. Here we report results from 126 treatment-naive people with HIV-1 who initiated DTG/3TC as part of a test-and-treat strategy (n = 61) or with high baseline viral loads (HIV-1 RNA ≥ 100,000 copies/ml; n = 16) from the TANDEM study. TANDEM was a US-based, retrospective chart review study that included a cohort of 126 individuals aged ≥ 18years with no prior history of ART who initiated DTG/3TC before September 30, 2020, and had ≥ 6months of follow-up. Test-and-treat was defined as ART initiation shortly after diagnosis without available viral load, CD4 + cell count, or HIV-1 resistance data. Outcomes included virologic suppression (HIV-1 RNA < 50 copies/ml; overall and by baseline viral load) and discontinuations. Analyses were descriptive. Among 61 individuals who initiated DTG/3TC in a test-and-treat setting (median [interquartile range (IQR)] treatment duration, 1.3 [0.9-1.7] years), 57 (93%) achieved virologic suppression, and 51 (84%) remained suppressed; 1 (< 1%) individual discontinued DTG/3TC due to persistent low-level viremia. The most common healthcare provider (HCP)-reported reason for initiating DTG/3TC was avoidance of long-term toxicities among individuals in the test-and-treat subgroup. Of 16 treatment-naive individuals with high baseline viral loads (median [IQR] treatment duration, 100,000-250,000 copies/ml: 1.2 [0.8-1.8] years; > 250,000 copies/ml: 1.0 [0.7-1.1] years), 14 (88%) achieved virologic suppression, 13 (81%) remained suppressed, and none discontinued DTG/3TC. Patient preference was the most common HCP-reported reason for initiating DTG/3TC in this subgroup. Results demonstrate real-world effectiveness of DTG/3TC, with few discontinuations, in people with HIV-1 in test-and-treat settings or with high baseline viral loads.

Abstract 982: Variation of cell-free DNA concentrations in liquid biopsies

Abstract Introduction: Liquid biopsies are promising noninvasive tools for cancer detection. Variation in cell-free DNA concentrations (cfDNA-conc) has been observed between individuals with and without cancer. We assessed cfDNA-conc in 2287 treatment-naive individuals including those without cancer, with benign or high-risk conditions, or with one of eight cancer types. Methods: Plasma (0.3 to 9.8 mL) was separated from whole blood collected in Streck or EDTA tubes from individuals with bile duct, breast, colorectal, gastric, ovarian, liver, lung, pancreatic, or metastatic cancer (n=23, 54, 28, 26, 264, 75, 180, 31, 22, respectively) as well as benign or high-risk conditions (n=550, 133, respectively) such as cirrhosis or hepatitis B or C virus infection (HBV/HCV), and without cancer (n=901). cfDNA was extracted using the Qiagen QIAamp Circulating Nucleic Acid Kit. Quality and quantity were assessed using the High Sensitivity DNA assay on the Agilent Bioanalyzer. Total amount (ng) of cfDNA from all nucleosomal peaks was evaluated per volume (mL) of plasma to assess significance across cohorts using unpaired two-sample Wilcoxon tests. Results: We observed that in individuals without cancer, cfDNA-conc increased with age (Pearson R2=0.59; 18-40yrs vs 41-55yrs, vs 56-65yrs, vs 66-85yrs; p=2.31E-09, 1.50E-12, 8.31E-17, respectively). No difference was observed between cfDNA-conc from EDTA and Streck plasma from the same individual (n=9, p=0.359, Wilcoxon signed-rank test two-tailed). Individuals with benign adnexal masses or cirrhosis had similar cfDNA-conc compared to those without cancer while individuals with benign lung lesions or HBV/HCV had significantly different cfDNA-conc (p=0.70, 0.35, 6.96E-04, 1.88E-09, respectively). These observations were not affected by age. Individuals with cancer had significantly higher cfDNA-conc compared to those without cancer (bile duct p=2.08E-14, breast p=4.44E-16, colorectal p=6.04E-10, gastric p=5.93E-04, ovarian p=9.99E-16, liver p=1.22E-15, lung p=0, pancreatic p=8.57E-03, metastatic p=1.18E-06). Ovarian cancer exhibited higher cfDNA-conc than benign adnexal masses which was more pronounced in later stage disease (I/II p=3.83E-06, III/IV p=8.18E-08). Compared to cirrhosis or HBV/HCV we observed a stepwise increase in cfDNA-conc in liver cancer with progressing stage (0/A p= 6.50E-04, B p= 5.69E-10, C p= 1.47E-08). Higher cfDNA-conc were also observed with higher stage of lung cancer compared to benign lung lesions (I/II p=4.99E-03, III/IV p=3.89E-06). Using cfDNA-conc (ng/mL) as a single feature, we distinguished individuals with and without cancer with an AUC of 0.72 (95% CI=0.70-0.75). Conclusions: In a cohort of 2287 individuals, we observed cfDNA-conc increases with age and cancer stage that varied across cancer types. As a classifier, cfDNA-conc can be predictive of cancer status, yet further work is needed to understand the contribution of other comorbidities. Citation Format: Sarah Short, Akshaya V. Annapragada, Jamie E. Medina, Zachariah H. Foda, Dimitrios Mathios, Carolyn Hruban, Elaine J. Chiao, Kavya Boyapati, Adrianna Bartolomucci, Keerti Boyapati, Vilmos Adleff, Robert B. Scharpf, Victor E. Velculescu, Jillian Phallen. Variation of cell-free DNA concentrations in liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 982.

Increased platelet-CD8+ T-cell aggregates displaying high activation, exhaustion, and tendency to death correlate with disease progression in people with HIV-1.

Platelets engage in HIV-1 infection by interacting with immune cells, which has been realized broadly. However, the potential interaction between platelets and CD8+ T cells remains unidentified. Here, treatment-naive individuals with HIV-1, complete immunological responders to antiretroviral therapy, and healthy controls were enrolled. First, we found that treatment-naive individuals with HIV-1 had low platelet numbers and high CD8+ T-cell counts when compared with complete immunological responders to antiretroviral therapy and healthy controls, leading to a low platelet/CD8+ T-cell ratio in peripheral blood, which could effectively differentiate the status of HIV-1 infection. Moreover, cytokines that may have been derived from platelets were higher in the plasma of people with HIV-1 despite viral suppression. Furthermore, we demonstrated that platelet-CD8+ T-cell aggregates were elevated in treatment-naive individuals with HIV-1, which positively correlated with HIV-1 viral load but negatively correlated with CD4+ T-cell count and CD4/CD8 ratio. Finally, we revealed that platelet-CD8+ T-cell aggregates correlate with enhanced activation/exhaustion and pyroptosis/apoptosis compared with free CD8+ T cells. Moreover, platelet-induced caspase 1 activation of CD8+ T cells correlated with IL-1β and IL-18 plasma levels. In brief, we reveal the importance of platelets in HIV-1 infection, which might secrete more cytokines and mediate CD8+ T-cell phenotypic characteristics by forming platelet-CD8+ T-cell aggregates, which are related to poor prognosis.

A prospective, observational, multicentre study to evaluate the efficacy of brivaracetam as adjuvant therapy for epilepsy: The Bravo study.

Epilepsy is a persistent tendency to experience epileptic seizures and can lead to various neurobiological disorders, with an elevated risk of premature mortality. This study evaluates the efficacy of brivaracetam adjuvant therapy in patients with epilepsy. A prospective observational multicentre study that was conducted in Pakistan from March to September 2022, by using a non-probability convenience sampling technique. The population consisted of 543 individuals with a diagnosis of epilepsy for whom adjunctive brivaracetam (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) was recommended by the treating physician. The research sample was drawn from various private neurology clinics of Karachi, Lahore, Rawalpindi, Islamabad and Peshawar. Data originating from routine patient visits, and assessments at three study time points, were recorded in the study case report form. Across 18 clinical sites, 543 individuals participated, with a mean age of 32.9 years. The most prescribed dosages were 50 mg BD, followed by 100 mg BD. Notably, brivaracetam combined with divalproex sodium was the most prevalent treatment, followed by brivaracetam with levetiracetam. At both the 14th and 90th day assessments, a significant reduction in seizure frequency was observed, with 63.1% of individuals showing a favourable response by day 90. Treatment-naive individuals exhibited higher rates of seizure freedom and response compared with treatment-resistant individuals. The study demonstrates the effectiveness of brivaracetam combination therapy in epilepsy management, with notable reductions in seizure frequency and favourable clinical responses observed, particularly in treatment-naive individuals.

Comparing Real-World Healthcare Costs Associated with Single-Tablet Regimens for HIV-1: The 2-Drug Regimen Dolutegravir/Lamivudine vs. Standard 3- or 4-Drug Regimens.

Dolutegravir/lamivudine (DTG/3TC) is a 2-drug regimen for HIV-1 treatment with long-term efficacy and good tolerability comparable to 3- or 4-drug regimens. This study evaluated DTG/3TC cost versus other standard single-tablet regimens during its first year of approval. This retrospective study analyzed US claims data from adults with HIV-1. Eligibility criteria included≥1 dispensing of DTG/3TC, DTG/abacavir (ABC)/3TC, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF, and darunavir (DRV)/COBI/FTC/TAF (index date was first dispensing) and≥6months of continuous eligibility before index date (baseline period). All-cause and HIV-related healthcare costs were evaluated during the observation period (index date until earliest of end of continuous eligibility or data availability). Adjusted cost differences and adjusted cost ratios were estimated using multivariable regression models controlling for differences in baseline characteristics between cohorts. Overall, 22,061 individuals with HIV-1 and dispensed treatment with DTG/3TC (n=590), DTG/ABC/3TC (n=4355), BIC/FTC/TAF (n=9068), EVG/COBI/FTC/TAF (n=7081), or DRV/COBI/FTC/TAF (n=967) were included. Most claims data were from men (mean age~46years). Mean unadjusted all-cause total healthcare costs per patient per month were significantly lower for DTG/3TC versus BIC/FTC/TAF and DRV/COBI/FTC/TAF, and mean unadjusted HIV-related healthcare costs per patient per month were significantly lower for DTG/3TC versus DRV/COBI/FTC/TAF. Cost differences were primarily driven by significantly lower pharmacy costs for DTG/3TC versus other regimens (P<0.001), while medical costs were similar across cohorts. Results were similar among treatment-naive and treatment-experienced individuals. After adjusting for baseline covariates, significant adjusted cost differences were generally consistent with unadjusted findings. Adjusted cost ratios generally favored DTG/3TC for all-cause healthcare and HIV-related costs, with all pharmacy cost ratios favoring DTG/3TC (P<0.001). Dolutegravir/lamivudine had the lowest healthcare costs of BIC/FTC/TAF, EVG/COBI/FTC/TAF, and DRV/COBI/FTC/TAF, and the lowest pharmacy costs of all regimens, in unadjusted and adjusted analyses and by treatment experience, supporting the economic benefits of DTG/3TC as an initial or switch regimen for HIV-1.

MicroRNA Expression Levels in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus Type 1 Positive Individuals and Relationship with Different Levels of Viral Suppression.

The persistence of low human immunodeficiency virus type 1 (HIV-1) replication in individuals undergoing antiretroviral therapy (ART) still threatens their health. Previous findings have shown that microRNAs (miRNAs) could interfere with several steps of the viral life cycle. Herein, we set out to investigate the expression of miR-150, miR-223, miR-382, miR-324-5p, miR-33a-5p, miR-34a, and miR-132 in the whole peripheral blood mononuclear cell (PBMC) population from people living with HIV-1 showing different levels of viral suppression. Levels of PBMC-associated miRNAs were analyzed in 30 individuals with undetectable viremia (target not detected) and 30 individuals with detectable low-level viremia (1-200 copies/mL). In addition, 30 samples from treatment-naive (NAIVE) individuals were investigated. Results were compared to a control group of 28 HIV-negative donors. All miRNAs analyzed were strongly downregulated in the NAIVE population, either compared to the treated group or to controls. Stratification of ART-treated donors according to the therapeutic regimen showed the downregulation of miR-33a-5p in subjects treated with non-nucleoside reverse transcriptase inhibitors compared with those treated with protease inhibitors. Collectively, the present study shows that uncontrolled viral replication leads to profound miRNA deregulation while treated individuals, irrespective of the degree of viral suppression, and even the types of antiviral drugs seem to be specifically associated with miRNA expression profiles. These evidences suggest that virological suppression could be favored by miRNA modulation.

Modelling the impact of treatment adherence on the transmission of HIV drug resistance.

A lower adherence rate (percentage of individuals taking drugs as prescribed) to ART may increase the risk of emergence and transmission of HIV drug resistance, decrease treatment efficacy, and increase mortality rate. Exploring the impact of ART adherence on the transmission of drug resistance could provide insights in controlling the HIV epidemic. We proposed a dynamic transmission model incorporating the CD4 cell count-dependent rates of diagnosis, treatment and adherence with transmitted drug resistance (TDR) and acquired drug resistance. This model was calibrated and validated by 2008-2018 HIV/AIDS surveillance data and prevalence of TDR among newly diagnosed treatment-naive individuals from Guangxi, China, respectively. We aimed to identify the impact of adherence on drug resistance and deaths during expanding ART. In the base case (ART at 90% adherence and 79% coverage), we projected the cumulative total new infections, new drug-resistant infections, and HIV-related deaths between 2022 and 2050 would be 420 539, 34 751 and 321 671. Increasing coverage to 95% would reduce the above total new infections (deaths) by 18.85% (15.75%). Reducing adherence to below 57.08% (40.84%) would offset these benefits of increasing coverage to 95% in reducing infections (deaths). Every 10% decrease in adherence would need 5.07% (3.62%) increase in coverage to avoid an increase in infections (deaths). Increasing coverage to 95% with 90% (80%) adherence would increase the above drug-resistant infections by 11.66% (32.98%). A decrease in adherence might offset the benefits of ART expansion and exacerbate the transmission of drug resistance. Ensuring treated patients' adherence might be as important as expanding ART to untreated individuals.

HIV-1 infection in South Kivu (Democratic Republic of Congo): high genotypic resistance to antiretrovirals.

Panzi General Reference Hospital (HGR Panzi) in the Democratic Republic of Congo follows a large number of patients living with HIV-1 (PLWHIV). Although antiretrovirals (ARVs) are available, HIV-1 viral load (HIV-VL) measurement has only been implemented in the hospital since 2018. No data on ARV resistance levels and ARV dosage in plasma have yet been published for this region. We determined the prevalence of virological failure due to ARV resistance amongst patients and assessed the degree of genotypic resistance of the viral strains. We performed an HIV-VL test and determined dosage of ARVs on samples collected from 205 PLWHIV at HGR Panzi between 2017 and 2018, including 13 ARV-naive patients. Genotypic resistance testing was performed on all samples with detectable HIV-VLs, and interpreted with the Agence Nationale de Recherches sur le Sida (ANRS) 2018 algorithm. Baseline resistance to NNRTIs was found in 2 of the 13 treatment-naive individuals (15%). ARV dosage was non-optimal for 44/192 of treated patients (22.9%), with an HIV-VL ≥1000 IU/mL for 40/192 (20.8%) of them. In particular, treatment-experienced viruses presented resistance to at least one NRTI (52.5%), to at least one NNRTIs (70%) or to at least one PIs (15%). Finally, two samples contained viruses with resistance polymorphism in the integrase gene. The high level of resistance to ARVs observed during this study, mainly due to treatment compliance default, fully justifies the implementation of means for closer patient monitoring. The provision of VL tests and therapeutic education management tools in a PLWHIV follow-up remains an absolute necessity to best adapt the current treatment lines in this region.

Molecular testing-guided therapy versus susceptibility testing-guided therapy in first-line and third-line Helicobacter pylori eradication: two multicentre, open-label, randomised controlled, non-inferiority trials

Helicobacter pylori infection is an important causal factor of gastric cancer and peptic ulcer disease and is associated with immune thrombocytopenic purpura and functional dyspepsia. In H pylori strains, point mutations in the 23S rRNA and gyrA genes are associated with clarithromycin resistance and levofloxacin resistance, respectively. Whether the efficacy of molecular testing-guided therapy is non-inferior to that of susceptibility testing-guided therapy for H pylori eradication is unclear. Therefore, we aimed to compare the efficacy and safety of molecular testing-guided therapy and traditional culture-based susceptibility testing-guided therapy in first-line and third-line treatment of H pylori infection. We did two multicentre, open-label randomised trials in Taiwan. In trial 1 (done at seven hospitals), treatment-naive individuals infected with H pylori who were aged 20 years or older were eligible for study inclusion. In trial 2 (done at six hospitals), individuals aged 20 years or older who failed treatment after two or more eradication therapies for H pylori infection were eligible for enrolment. Eligible patients were randomly assigned (1:1) to receive either molecular testing-guided therapy or susceptibility testing-guided therapy. The randomisation sequence was generated by computer using permuted block randomisation with a block size of 4. All investigators were masked to the randomisation sequence. Clarithromycin and levofloxacin resistance were determined by agar dilution test for measuring minimum inhibitory concentrations in the susceptibility testing-guided therapy group, and by PCR and direct sequencing for detection of 23S rRNA and gyrA mutations in the molecular testing-guided therapy group. Study participants received clarithromycin sequential therapy, levofloxacin sequential therapy, or bismuth quadruple therapy according to the resistance status to clarithromycin and levofloxacin. The 13C-urease breath test was used to determine the status of H pylori infection at least 6 weeks after eradication therapy. The primary outcome was the eradication rate by intention-to-treat analysis. The frequency of adverse effects was analysed in patients with available data. The prespecified margins for non-inferiority were 5% for trial 1 and 10% for trial 2. The trials are ongoing for post-eradication follow-up and registered with ClinicalTrials.gov, NCT03556254 for trial 1, and NCT03555526 for trial 2. Between March 28, 2018, and April 23, 2021, 560 eligible treatment-naive patients with H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 1. Between Dec 28, 2017, and Oct 27, 2020, 320 eligible patients with refractory H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 2. 272 men and 288 women were recruited for trial 1, and 98 men and 222 women were recruited for trial 2. In first-line H pylori treatment, infection was eradicated in 241 (86%, 95% CI 82-90) of 280 patients in the molecular testing-guided therapy group and 243 (87%, 83-91) of 280 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·81). In third-line H pylori treatment, infection was eradicated in 141 (88%, 83-93) of 160 patients in the molecular testing-guided therapy group and 139 (87%, 82-92) of 160 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·74). The difference in the eradication rate between the molecular testing-guided therapy group and the susceptibility testing-guided therapy group was -0·7% (95% CI -6·4 to 5·0; non-inferiority p=0·071) in trial 1 and 1·3% (-6·0 to 8·5; non-inferiority p=0·0018 in trial 2 by intention-to-treat analysis. We found no difference in adverse effects across both treatment groups in trial 1 and trial 2. Molecular testing-guided therapy was similar to susceptibility testing-guided therapy in first-line therapy and non-inferior to susceptibility testing guided therapy in third-line treatment of H pylori infection, supporting the use of molecular testing-guided therapy for H pylori eradication. Ministry of Science and Technology of Taiwan, and Centre of Precision Medicine of the Higher Education Sprout Project by the Ministry of Education of Taiwan.

Depressive symptoms, anxiety and social stress are associated with diminished cardiovascular reactivity in a psychological treatment-naive population

BackgroundThere is now an increasing appreciation of how psychological health can contribute to cardiovascular disease, called the mind-heart connection. A blunted cardiovascular reactivity to depression and anxiety may be responsible for the potential mechanism, however, with inconsistent results. Anti-psychological drugs have an effect on the cardiovascular system and, thus, may disturb their relationship. However, in treatment-naive individuals with psychological symptoms, no research has specifically evaluated the relationship between psychological state and cardiovascular reactivity. MethodsWe included 883 treatment-naive individuals who came from a longitudinal cohort study of Midlife in the United States. Symptoms of depression, anxiety, and stress were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D), Spielberger Trait Anxiety Inventory (STAI), the Liebowitz Social Anxiety scale (LSAS) and the Perceived Stress Scale (PSS), respectively. Cardiovascular reactivity was measured using standardized, laboratory-based stressful tasks. ResultsTreatment-naive individuals with depressive symptoms (CES-D ≥ 16), anxiety symptoms (STAI ≥ 54), and higher stress levels (PSS ≥ 27) had lower cardiovascular reactivity as assessed by systolic blood pressure (SBP) reactivity, diastolic blood pressure (DBP) reactivity and heart rate (HR) reactivity (P < 0.05). Pearson analyses showed that psychological symptoms were correlated with lower SBP reactivity, DBP reactivity, and heart rate reactivity (P < 0.05). Multivariate linear regression showed that depression and anxiety were negatively related to lower cardiovascular reactivity (SBP, DBP and HR reactivity) after full adjustments (P < 0.05). Stress was associated with reduced SBP and DBP reactivity but with a nonsignificant association with HR reactivity (P = 0.056). ConclusionDepression, anxiety, and stress symptoms are associated with blunted cardiovascular reactivity in treatment-naive adult Americans. These findings suggest that blunted cardiovascular reactivity is an underlying mechanism linking psychological health and cardiovascular diseases.

The impact of attrition on the transmission of HIV and drug resistance: A mathematical modelling study.

Attrition due to loss to follow-up or termination of antiretroviral therapy (ART) among HIV-infected patients in care may increase the risk of emergence and transmission of drug resistance (TDR), diminish benefit of treatment, and increase morbidity and mortality. Understanding the impact of attrition on the epidemic is essential to provide interventions for improving retention in care. We developed a comprehensive HIV transmission dynamics model by considering CD4+ cell count dependent diagnosis, treatment, and attrition involving TDR and acquired drug resistance. The model was calibrated by 11 groups HIV/AIDS surveillance data during 2008-2018 from Guangxi, China, and validated by the prevalence of TDR among diagnosed treat-naive individuals. We aimed to investigate how attrition would affect the transmission of HIV and drug-resistance when expanding ART. In the base case with CD4+ cell count dependent per capita attrition rates 0.025∼0.15 and treatment rates 0.23∼0.42, we projected cumulative total new infections, new drug-resistant infections, and HIV-related deaths over 2022-2030 would be 145 391, 7637, and 51 965, respectively. Increasing treatment rates by 0.1∼0.2 can decrease the above total new infections (deaths) by 1.63∼2.93% (3.52∼6.16%). However, even 0.0114∼0.0220 (0.0352∼0.0695) increase in attrition rates would offset this benefit of decreasing infections (deaths). Increasing treatment rates (attrition rates) by 0.05∼0.1 would increase the above drug-resistant infections by 0.16∼0.30% (22.18∼41.15%). A minor increase in attrition can offset the benefit of treatment expansion and increase the transmission of HIV drug resistance. Reducing attrition rates for patients already in treatment may be as important as expanding treatment for untreated patients.

Dynamics of Rilpivirine Resistance-Associated Mutation: E138 in Reverse Transcriptase among Antiretroviral-Naive HIV-1-Infected Individuals in Turkey.

Rilpivirine, one of the non-nucleoside reverse transcriptase inhibitors class anti-HIV agents, is used as an alternative drug to treat HIV-1-positive individuals according to current antiretroviral therapy (ART) guidelines. Mutation in the position E138 in HIV-1 reverse transcriptase (RT) leads to resistance to rilpivirine, alone reducing its susceptibility two to threefolds. The main aim of this study was to determine the dynamics of E138 mutation in the RT domain of the HIV-1 pol gene; in 6398 newly diagnosed and treatment-naive individuals in Turkey from 2013 to 2021. Rilpivirine-associated mutations were found among 424 (6.6%) out of 6398. Individuals with the E138 mutation had significantly higher HIV-1 RNA load than individuals without the E138 mutation (p = .044). The E138 mutation was mainly observed in the B subtype (40%) of HIV-1 compared to the non-B subtypes (26.9%) and the circulating recombinant forms (33.1%) (p < .001). Most E138 mutations were E138A (80%), followed by E138G (16.5%). This study uncovered the dynamics of rilpivirine-associated mutations over a long period and a large patient population. Before administering ART regimens consisting of rilpivirine, resistance monitoring is highly recommended for effective patient management in the treatment-of naive HIV-1-infected individuals.

HIV-1 Subtype C Vpr Amino Acid Residue 45Y and Specific Conserved Fragments Are Associated with Neurocognitive Impairment and Markers of Viral Load.

There is increasing evidence that HIV-1 viral protein R (Vpr) plays an important role in the pathogenesis of cognitive impairment. We investigated the relationship between HIV-1 subtype C Vpr sequence variation and HIV-associated neurocognitive impairment as measured by global deficit score (GDS) in treatment-naive individuals. We used different bioinformatic tools and statistical models to correlate vpr variation and cognitive function. We identified a tyrosine at position 45 (45Y) as a signature for neurocognitive impairment and histidine (45H) as a signature in the non-impaired individuals. The presence of signature 45Y was associated by 3.66 times higher GDS, 525 times higher plasma viral load, 15.84 times higher proviral load, and 60% lower absolute CD4-T cell count compared with those without the signature. Additionally, we identified four conserved Vpr fragment sequences, PEDQGPQREPYNEWTLE (5-21), LGQYIY (42-47), TYGDTW (49-54), and PEDQGPQREPYNEW (5-18), that were associated with higher plasma viral load and proviral load. The implication of these findings is that variation of Vpr leads to neurocognitive impairment in HIV infection and worsens the progression of disease in general by promoting the production of provirus, promoting HIV replication and depletion of CD4+ T cells in the periphery.

Prevalence of Cytopenia and its Correlation with Immunosuppression in Naïve HIV-1 Infected Patients Initiating First-Line Antiretroviral Therapy: A Pilot Study.

Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency virus (HIV) infection. This study aimed to assess the prevalence of cytopenias and their correlation with the level of immunosuppression in treatment-naive HIV-infected participants after initiating highly active combined antiretroviral drug therapy (cART24). This prospective study focused on evaluating cytopenia in 44 treatment-naive HIV-infected patients who consented to initiate cART and were consecutively enrolled. The research was conducted at the Nasara HIV Treatment &amp; Care Centre of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria, spanning from December 2016 to January 2018. Cytopenias, including anemia, leucopenia, lymphocytopenia, and thrombocytopenia, were defined and assessed according to World Health Organization guidelines. A combination of cross-sectional and longitudinal mixed-design two-step analysis was employed to validate our findings. The median time from enrollment to cART initiation was 7 days, following the universal test and treat protocol. The prevalence of cytopenia was 75% at the baseline before treatment and increased to 84% after cART24 administration. There were no statistically significant differences in the median values of immuno-hematological parameters between baseline and after cART24 initiation (P >0.05). In terms of longitudinal assessment, the prevalence of anemia, leucopenia, lymphopenia, and thrombocytopenia at baseline were 66%, 23%, 0%, and 11%, respectively, and after cART24, the rates were 66%, 29%, 5%, and 20%. Notably, the prevalence of cytopenia correlated with declining CD4+ T cell counts. Among instances of unicytopenia, 58% exhibited isolated anemia, 6% had lone leucopenia, and 6% had solitary thrombocytopenia. Additionally, 27% demonstrated bi-cytopenia, and 3% exhibited pancytopenia. Interestingly, none of the study participants presented with lymphopenia. The most common combination was anemia and thrombocytopenia. Both longitudinal and cross-sectional analytical findings were consistent. In treatment-naive HIV-infected individuals, the prevalence of cytopenias, particularly anemia and thrombocytopenia, was substantial and correlated with the degree of immunosuppression as indicated by CD4+ T cell counts. These cytopenias persisted despite initiation of cART24, highlighting the complexity of hematological manifestations in HIV infection. Our study underscores the significant hematopathological impact of HIV and antiretroviral therapy, highlighting the necessity for preventive strategies to mitigate these adverse effects.

Control of HIV-1 Replication by CD8+ T Cells Specific for Two Novel Pol Protective Epitopes in HIV-1 Subtype A/E Infection.

ABSTRACTAlthough many HIV-1-specific CD8+ T cell epitopes have been identified and used in various HIV-1 studies, most of these epitopes were derived from HIV-1 subtypes B and C. Only 17 well-defined epitopes, none of which were protective, have been identified for subtype A/E infection. The roles of HIV-1-specific T cells have been rarely analyzed for subtype A/E infection. In this study, we identified six novel HLA-B*15:02-restricted optimal HIV-1 subtype A/E epitopes and then analyzed the presentation of these epitopes by HIV-1 subtype A/E virus-infected cells and the T cell responses to these epitopes in treatment-naive HIV-1 subtype A/E-infected HLA-B*15:02+ Vietnamese individuals. Responders to the PolTY9 or PolLF10 epitope had a significantly lower plasma viral load (pVL) than nonresponders among HLA-B*15:02+ individuals, whereas no significant difference in pVL was found between responders to four other epitopes and nonresponders. The breadth of T cell responses to these two Pol epitopes correlated inversely with pVL. These findings suggest that HLA-B*15:02-restricted T cells specific for PolTY9 and PolLF10 contribute to the suppression of HIV-1 replication in HLA-B*15:02+ individuals. The HLA-B*15:02-associated mutation Pol266I reduced the recognition of PolTY9-specific T cells in vitro but did not affect HIV-1 replication by PolTY9-specific T cells in Pol266I mutant virus-infected individuals. These findings indicate that PolTY9-specific T cells suppress replication of the Pol266I mutant virus even though the T cells selected this mutant. This study demonstrates the effective role of T cells specific for these Pol epitopes to control circulating viruses in HIV-1 subtype A/E infection.IMPORTANCE It is expected that HIV-1-specific CD8+ T cells that effectively suppress HIV-1 replication will contribute to HIV-1 vaccine development and therapy to achieve an HIV cure. T cells specific for protective epitopes were identified in HIV-1 subtype B and C infections but not in subtype A/E infection, which is epidemic in Southeast Asia. In the present study, we identified six T cell epitopes derived from the subtype A/E virus and demonstrated that T cells specific for two Pol epitopes effectively suppressed HIV-1 replication in treatment-naive Vietnamese individuals infected with HIV-1 subtype A/E. One of these Pol protective epitopes was conserved among circulating viruses, and one escape mutation was accumulated in the other epitope. This mutation did not critically affect HIV-1 control by specific T cells in HIV-1 subtype A/E-infected individuals. This study identified two protective Pol epitopes and characterized them in cases of HIV-1 subtype A/E infection.

Regional metabolic heterogeneity in anterior cingulate cortex in major depressive disorder: A multi-voxel 1H magnetic resonance spectroscopy study

BackgroundPrevious studies have shown major depressive disorder (MDD) is associated with altered neuro-metabolites in the anterior cingulate cortex (ACC). However, the regional metabolic heterogeneity in the ACC in individuals with MDD remains unclear. MethodsWe recruited 59 first-episode, treatment-naive young adults with MDD and 50 healthy controls who underwent multi-voxel 1H-MRS scanning at 3 T (Tesla) with voxels placed in the ACC, which was divided into two subregions, pregenual ACC (pACC) and anterior midcingulate cortex (aMCC). Between and within-subjects metabolite concentration variations were analyzed with SPSS. ResultsCompared with control subjects, patients with MDD exhibited higher glutamate (Glu) and glutamine (Gln) levels in the pACC and higher myo-inositol (MI) level in the aMCC. We observed higher Glu and Gln levels and lower N-acetyl-aspartate (NAA) level in the pACC than those in the aMCC in both MDD and healthy control (HC) groups. More importantly, the metabolite concentration gradients of Glu, Gln and NAA were more pronounced in MDD patients relative to HCs. In the MDD group, the MI level in the aMCC positively correlated with the age of onset. LimitationsThe use of the relative concentration of metabolites constitutes a key study limitation. ConclusionsWe observed inconsistent alterations and distribution of neuro-metabolites concentration in the pACC and aMCC, revealing regional metabolic heterogeneity of ACC in first-episode, treatment-naive young individuals with MDD. These results provided new evidence for abnormal neuro-metabolites of ACC in the pathophysiology of MDD and suggested that pACC and aMCC might play different roles in MDD.

HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific Tcell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection.

Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human immunodeficiency virus type 1 (HIV-1). Whether they impact the immunological and neuropsychiatric profile differentially remains unclear. This retrospective analysis included 258 participants enrolled during acute HIV-1 infection (AHI). Participants initiated 1 of 3 ART regimens during AHI: EFV-based (n = 131), DTG-based (n = 92), or DTG intensified with maraviroc (DTG/MVC, n = 35). All regimens included 2 nucleoside reverse-transcriptase inhibitors and were maintained for 96 weeks. CD4+ and CD8+ T-cell counts, mood symptoms, and composite score on a 4-test neuropsychological battery (NPZ-4) were compared. At baseline, the median age was 26 years, 99% were male, and 36% were enrolled during Fiebig stage I-II. Plasma viral suppression at weeks 24 and 96 was similar between the groups. Compared with the EFV group, the DTG group showed greater increments of CD4+ (P < .001) and CD8+ (P = .015) T-cell counts but a similar increment of CD4/CD8 ratio at week 96. NPZ-4 improvement was similar between the 2 groups at week 24 but greater in the DTG group at week 96 (P = .005). Depressive mood and distress symptoms based on the Patient Health Questionnaire and distress thermometer were similar between the 2 groups at follow-up. Findings for the DTG/MVC group were comparable to those for the DTG group vs the EFV group. Among individuals with AHI, 96 weeks of DTG-based ART was associated with greater increments of CD4+ and CD8+ T-cell counts and improvement in cognitive performance.

Predictive value of CD8+ T cell and CD4/CD8 ratio at two years of successful ART in the risk of AIDS and non-AIDS events.

SummaryBackgroundWhile increased CD8 counts and low CD4/CD8 ratio during treated HIV correlate with immunosenescence, their additional predictive values to identify individuals with HIV at higher risk of clinical events remain controversial.MethodsWe selected treatment-naive individuals initiating ART from ACTG studies 384, 388, A5095, A5142, A5202, and A5257 who had achieved viral suppression at year 2. We examined the effect of CD8+ T cell counts and CD4/CD8 at year 2 on the probability of AIDS and serious non-AIDS events in years 3−7. We used inverse probability weighting methods to address informative censoring, combined with multivariable logistic regression models.FindingsWe analyzed 5133 participants with a median age of 38 years; 959 (19%) were female, pre-ART median CD4 counts were 249 (Q1-Q3 91–372) cell/µL. Compared to participants with CD8 counts between 500/µL and 1499/µL, those with >1500/µL had a higher risk of clinical events during years 3−7 (aOR 1.75; 95%CI 1.33−2.32). CD4/CD8 ratio was not predictive of greater risk of events through year 7. Additional analyses revealed consistent CD8 count effect sizes for the risk of AIDS events and noninfectious non-AIDS events, but opposite effects for the risk of severe infections, which were more frequent among individuals with CD8 counts <500/µL (aOR 1.70; 95%CI 1.09−2.65).InterpretationThe results of this analysis with pooled data from clinical trials support the value of the CD8 count as a predictor of clinical progression. People with very high CD8 counts during suppressive ART might benefit from closer monitoring and may be a target population for novel interventions.FundingThis research was supported by NIH/NIAID awards UM1 AI068634, UM1 AI068636, and UM1 AI106701 and Carlos III Health Institute and FEDER funds (BA21/00017 and BA21/00022).

Glucose, urea, and creatinine laboratory tests in people starting antiretroviral therapy with dolutegravir or efavirenz: a cohort study in Belo Horizonte, Brazil

Goal: In this study, we aimed to monitor the blood glucose, urea, and creatinine laboratory tests in treatment-naive individuals, initiating ART with an antiretroviral regimen containing EFV or DTG, searching for a contribution to the understanding of the safety of these drugs in use in the real world, followed up for 72 weeks. Methods: Cohort study with a follow-up of people living with HIV initiating antiretroviral therapy. Results: An increase in blood creatinine levels at 24 and 48 weeks and blood glucose levels at 48 weeks (p=0.017) was observed in the group using Dolutegravir. Those using Efavirenz evidenced an increase in creatinine levels at 48 weeks (p=0.007), blood glucose levels at 72 weeks (p=0.009), and urea levels at 48 weeks (p=0.023). Being male (p=0.044) and having more than 13 schooling years (0.044) explained the change in creatinine levels. Tobacco use (p=0.006), illicit drug use (p=0.009), and schooling greater than or equal to 13 study years (p=0.038) were independently associated with changes in urea levels. The therapeutic regimen with Efavirenz (OR=8.20; 95% CI=1.32-51.05; p=0.024) and schooling greater than or equal to 13 study years were independently associated with increased blood glucose concentration. Conclusions: The DTG regimen was associated with increased serum creatinine levels for up to 42 weeks and was transient and returning to the levels observed before the start of ART. The Efavirenz regimen was related to increased serum glucose levels, and the Dolutegravir therapy was the preferred regimen.