Validation of new potential targets for remission and low disease activity in psoriatic arthritis in patients treated with golimumab.

OBJECTIVES: Treat to target recommendations for PsA state that the target of treatment should be remission or, at the very least, low disease activity. Different clinical indexes have been proposed to define these disease states including the minimal disease activity criteria and the Disease Activity Index for PsA (DAPSA) scores, which have 7 and 4-5 domains, respectively. Using a Canadian cohort, the objectives were to calculate the proportion of patients achieving these criteria, their prognostic value and the overall patient impact of these disease states. METHODS: BioTRAC is an ongoing, prospective registry of inflammatory arthritis patients. 188 PsA patients treated with golimumab were included. Data collected at baseline, 6 and 12 months were used. RESULTS: Between 15.6% and 38.3% of patients achieved remission, and 37.4-77.7% achieved low disease activity at 6 and 12 months' follow-up. Patients achieving any minimal disease activity target and DAPSA low disease activity had significantly lower swollen joint count, tender joint count, psoriasis area and severity index, dactylitis and enthesitis scores compared with non-achievers (P < 0.05). Higher HAQ scores (P < 0.03) were observed in patients achieving remission with remaining dactylitis or active skin disease. CONCLUSION: Very low disease activity was the most stringent new potential target for remission in PsA. There was a high level of agreement between scores, although residual activity in dactylitis and skin despite DAPSA remission may affect patient function. Patients achieving either DAPSA endpoint, however, did not show a significant reduction in skin disease, indicating that those two criteria are more restricted to joint symptoms.

The semen microbiome and its relationship with local immunology and viral load in HIV infection.

Semen is a major vector for HIV transmission, but the semen HIV RNA viral load (VL) only correlates moderately with the blood VL. Viral shedding can be enhanced by genital infections and associated inflammation, but it can also occur in the absence of classical pathogens. Thus, we hypothesized that a dysregulated semen microbiome correlates with local HIV shedding. We analyzed semen samples from 49 men who have sex with men (MSM), including 22 HIV-uninfected and 27 HIV-infected men, at baseline and after starting antiretroviral therapy (ART) using 16S rRNA gene-based pyrosequencing and quantitative PCR. We studied the relationship of semen bacteria with HIV infection, semen cytokine levels, and semen VL by linear regression, non-metric multidimensional scaling, and goodness-of-fit test. Streptococcus, Corynebacterium, and Staphylococcus were common semen bacteria, irrespective of HIV status. While Ureaplasma was the more abundant Mollicutes in HIV-uninfected men, Mycoplasma dominated after HIV infection. HIV infection was associated with decreased semen microbiome diversity and richness, which were restored after six months of ART. In HIV-infected men, semen bacterial load correlated with seven pro-inflammatory semen cytokines, including IL-6 (p = 0.024), TNF-α (p = 0.009), and IL-1b (p = 0.002). IL-1b in particular was associated with semen VL (r(2)  = 0.18, p = 0.02). Semen bacterial load was also directly linked to the semen HIV VL (r(2) = 0.15, p = 0.02). HIV infection reshapes the relationship between semen bacteria and pro-inflammatory cytokines, and both are linked to semen VL, which supports a role of the semen microbiome in HIV sexual transmission.

HIV-1 gp120 induces TLR2- and TLR4-mediated innate immune activation in human female genital epithelium.

Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

Impact of antiretroviral therapy duration and intensification on isolated shedding of HIV-1 RNA in semen.

BACKGROUND: Effective antiretroviral therapy (ART) dramatically reduces human immunodeficiency virus (HIV) transmission. However, isolated shedding of HIV type 1 (HIV-1) in semen (IHS) can occur in the absence of detectable viremia or genital infections. We hypothesized that ART intensification with medications active in semen might prevent IHS. METHODS: Paired blood and semen samples were collected monthly for 6 months from HIV-infected men starting ART that was intensified (iART) with maraviroc and raltegravir in an open-label fashion. Semen parameters were compared to those of historical controls starting standard ART (sART). RESULTS: Compared with 25 controls who started sART, the semen HIV-1 load in 13 subjects who started iART was more rapidly suppressed (P = .043). IHS was detected at >1 visit in 2 participants (15%) receiving iART and in 12 controls (48%) receiving sART (P = .040). Among iART recipients, IHS was associated with lower raltegravir concentrations in blood and semen, compared with complete HIV-1 suppression (P = .03). Prolonged, high-level IHS (ie, shedding of >5000 RNA copies/mL) was observed in 1 iART recipient (8%), despite rapid viremia suppression and therapeutic drug levels; for 10 months, this virus remained R5 tropic, drug susceptible, and similar in sequence to virus recovered from blood. IHS was not seen after >3 years of effective ART in a parallel, prospective cohort study. CONCLUSIONS: iART transiently reduced the occurrence of IHS early after ART initiation but did not prevent high-level IHS. IHS was not seen after more prolonged sART.

Genetic testing practices among specialist physicians who treat prostate cancer A Canadian, cross-sectional survey.

INTRODUCTION: In patients with prostate cancer (PCa), the identification of an alteration in genes associated with homologous recombination repair (HRR) has implications for prognostication, optimization of therapy, and familial risk mitigation. The aim of this study was to assess the genomic testing landscape of PCa in Canada and to recommend an approach to offering germline and tumor testing for HRR-associated genes. METHODS: The Canadian Genitourinary Research Consortium (GURC) administered a cross-sectional survey to a largely academic, multidisciplinary group of investigators across 22 GURC sites between January and June 2022. RESULTS: Thirty-eight investigators from all 22 sites responded to the survey. Germline genetic testing was initiated by 34%, while 45% required a referral to a genetic specialist. Most investigators (82%) reported that both germline and tumor testing were needed, with 92% currently offering germline and 72% offering tissue testing to patients with advanced PCa. The most cited reasons for not offering testing were an access gap (50%), uncertainties around who to test and which genes to test, (33%) and interpreting results (17%). A majority reported that patients with advanced PCa (74-80%) should be tested, with few investigators testing patients with localized disease except when there is a family history of PCa (45-55%). CONCLUSIONS: Canadian physicians with academic subspecialist backgrounds in genitourinary malignancies recognize the benefits of both germline and somatic testing in PCa; however, there are challenges in accessing testing across practices and specialties. An algorithm to reduce uncertainty for providers when ordering genetic testing for patients with PCa is proposed.

Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada.

BACKGROUND: Management of advanced prostate cancer has evolved rapidly with the availability of multiple systemic treatments such as androgen-receptor axis-targeted therapies (ARATs), taxane-based chemotherapy, radium-223, and other approaches. However, limited data exists on real-world treatment selection and clinical outcomes. This study examines the utilization and survival impact of these therapies in men with metastatic castration-resistant prostate cancer (mCRPC) in the real-world setting of Ontario, Canada. METHODS: This study was a retrospective, longitudinal, population-based study of administrative claims data between January 2016 and April 2020. Men ≥ 66 years with mCRPC receiving advanced treatment were included. Patients were indexed on the day they initiated mCRPC treatment and followed up until death or end of study period to assess treatment and survival. Multinomial regression was used to model the association between baseline covariates, treatment and survival. RESULTS: Median age was 75 years among the 944 mCRPC patients who received life-prolonging therapies during this time period. Over 90% of patients used an ARAT as a first-line therapy, and 71.5% received only first-line therapy before death or censoring. Of patients that received two or more lines, over 80% received subsequent therapy with a different mechanism of action. Median overall survival was 18.9 months. CONCLUSIONS: ARATs have become the predominant first-line systemic treatment option for mCRPC patients in recent years. Notably, the majority of patients received only a single line of life-prolonging therapy after developing mCRPC. In keeping with the recognized efficacy-effectiveness gap, real-world outcomes in this cohort appear poorer than in clinical trials.

Patterns of care for non-metastatic castration-resistant prostate cancer: A population-based study.

Objectives: To describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous ADT for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Patients and Methods: This was a retrospective, longitudinal, population-based study of administrative health data from 2008 to 2019. Men 65 years and older receiving continuous androgen deprivation therapy (ADT) with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2-year look-back window was used to assess patterns of care leading up to CRPC as well as baseline covariates. Results: At a median follow-up of 40.1 months, 944 patients with nmCRPC were identified. Their median time from initiation of continuous ADT to CRPC was 26.0 months. 60.7% of patients had their PSA measured twice or fewer in the year prior to index, and 70.7% patients did not receive any imaging in the year following progression to CRPC. Throughout the study period, 921/944 (97.6%) patients with CRPC progressed to high-risk (HR-CRPC) with PSA doubling time ≤ 10 months, of which more than half received fewer than three PSA tests in the year prior to developing HR-CRPC, and 30.9% received no imaging in the subsequent year. Conclusion: PSA testing and imaging studies are underutilized in a real-world setting for the management of nmCRPC, including those at high risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging and detection of treatment failure and/or metastases, thereby delaying the necessary treatment intensification with life-prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patient outcomes.

Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry.

OBJECTIVE: To describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers. DESIGN: Biologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab. SETTING: 46 primary-care Canadian rheumatology practices. PARTICIPANTS: 223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: MDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient's global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression. RESULTS: MDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%). CONCLUSIONS: Almost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI. TRIAL REGISTRATION NUMBER: BioTRAC (NCT00741793).

Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men.

BACKGROUND: This study was done to characterize parameters associated with semen human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) viral load (VL) variability in HIV-infected, therapy-naive men. METHODS: Paired blood and semen samples were collected from 30 HIV-infected, therapy-naive men who have sex with men, and 13 participants were observed longitudinally for up to 1 year. Human immunodeficiency virus RNA, bacterial load by 16S RNA, herpesvirus (Epstein-Barr virus and cytomegalovirus [CMV]) shedding, and semen cytokines/chemokines were quantified, and semen T-cell subsets were assessed by multiparameter flow cytometry. RESULTS: Semen HIV RNA was detected at 93% of visits, with >50% of men shedding high levels of virus (defined as >5000 copies/mL). In the baseline cross-sectional analysis, an increased semen HIV VL correlated with local CMV reactivation, the semen bacterial load, and semen inflammatory cytokines, particularly interleukin (IL)-8. T cells in semen were more activated than blood, and there was an increased frequency of Th17 cells and γδ-T-cells. Subsequent prospective analysis demonstrated striking interindividual variability in HIV and CMV shedding patterns, and only semen IL-8 levels and the blood VL were independently associated with semen HIV levels. CONCLUSIONS: Several clinical and immune parameters were associated with increased HIV semen levels in antiretroviral therapy-naive men, with induction of local proinflammatory cytokines potentially acting as a common pathway.

Latent TGF-ß1 is compartmentalized between blood and seminal plasma of HIV-positive men and its activation in semen is negatively correlated with viral load and immune activation.

PROBLEM: Semen is the primary medium for sexual transmission of HIV-1 and contains high concentrations of TGF-ß1, but its role in regulating HIV-mediated immune activation is unclear. METHOD OF STUDY: TGF-ß1 and sCD14 were compared in blood plasma (BP) and seminal plasma (SP) from HIV-uninfected and infected, antiretroviral therapy (ART)-naive and ART-treated men and in THP-1 cells following exposure to HIV-1. The relationship between TGF-ß1 and sCD14 was determined by Spearman correlation. RESULTS: Active and latent forms of TGF-ß1 were compartmentalized between BP and SP. Highest active TGF-ß1 levels were present in SP of ART-naïve chronic-infected men and decreased following ART treatment. Latent TGF-ß1 was upregulated in BP following HIV infection, and highest levels were observed in BP of acute-infected men. Similar expression trends were observed between latent TGF-ß1 and sCD14 in BP. A significant negative correlation was observed between active TGF-ß1, sCD14, and semen viral load in ART-naive men. CONCLUSION: TGF-ß1 is compartmentalized between blood and semen, possibly co-expressed with sCD14 by activated monocytes/macrophages in BP as a result of HIV infection. Conversion of latent TGF-ß1 into its active form could contribute to regulation of viral load and immune activation in the male genital tract, but depends on the stage of infection.

Antiretroviral therapy in HIV-infected elite controllers: impact on gut immunology, microbial translocation, and biomarkers of serious non-AIDS conditions.

Elite controllers (ECs) maintain undetectable HIV viral loads without antiretroviral therapy (ART) but are at increased risk of serious non-AIDS conditions (SNA). We assessed the impact of ART in ECs on gut immune dysfunction and biomarkers predicting SNA (blood CD4/CD8 ratio, plasma IL-6, D-dimer levels). At baseline, ECs had elevated IL-6 and D-dimer levels and reduced CD4/CD8 ratio compared with HIV-uninfected controls, but no difference in microbial translocation or gut CD4 subsets. ART increased CD4/CD8 ratio but did not normalize IL-6 and D-dimer levels. EC SNA pathogenesis may be independent of gut immune dysfunction, and resolution may require prolonged ART.

Endometrial epithelial cell response to semen from HIV-infected men during different stages of infection is distinct and can drive HIV-1-long terminal repeat.

OBJECTIVES: Although more than 60% of HIV transmission occurs via semen, little is known about the immune impact of seminal plasma on HIV susceptibility. Here, we examined the level of selected immunomodulatory factors in seminal plasma from HIV-uninfected and therapy-naive, HIV-infected men in acute and chronic stages; the cytokine response elicited by seminal plasma in genital epithelial cells (GECs); and whether any GEC response to seminal plasma could drive HIV replication in infected T cells. METHODS: A panel of nine cytokines and chemokines was measured in seminal plasma from HIV-uninfected and HIV-infected men and in primary GEC cultures following seminal plasma exposure. HIV-long terminal repeat (LTR) activation was measured in 1G5 T cells exposed to supernatants from seminal plasma-treated GECs. RESULTS: Pro-inflammatory cytokines and chemokines were present at significantly higher levels in seminal plasma from acute men, whereas transforming growth factor (TGF)-ß1 was significantly higher in seminal plasma from chronic men. Pro-inflammatory cytokine production by GECs was significantly decreased following incubation with seminal plasma from chronic men. Blocking the TGF-ß1 receptor in GECs prior to seminal plasma exposure enhanced pro-inflammatory cytokine production. Exposure to seminal plasma activated nuclear factor (NF)-κB in GECs and blocking it significantly reduced pro-inflammatory cytokine production. GEC responses to seminal plasma, especially from acute men, significantly activated HIV-LTR activation in 1G5 T cells. CONCLUSION: Immunomodulatory factors in seminal plasma vary, depending on presence and stage of HIV infection. Exposure to seminal plasma leads to NF-κB activation and pro-inflammatory cytokine production, whereas TGF-ß in seminal plasma may suppress pro-inflammatory cytokine production by GECs. GEC responses to seminal plasma can activate HIV-LTR in infected CD4(+) T cells.

Impact of collection method on assessment of semen HIV RNA viral load.

BACKGROUND: The blood HIV RNA viral load is the best-defined predictor of HIV transmission, in part due to ease of measurement and the correlation of blood and genital tract (semen or cervico-vaginal) viral load, although recent studies found semen HIV RNA concentration to be a stronger predictor of HIV transmission. There is currently no standardized method for semen collection when measuring HIV RNA concentration. Therefore, we compared two collection techniques in order to study of the impact of antiretroviral therapy on the semen viral load. METHODOLOGY/PRINCIPAL FINDINGS: Semen was collected by masturbation from HIV-infected, therapy-naïve men who have sex with men (MSM) either undiluted (Visit 1) or directly into transport medium (Visit 2). Seminal plasma was then isolated, and the HIV RNA concentration obtained with each collection technique was measured and corrected for dilution if necessary. Collection of semen directly into transport medium resulted in a median HIV RNA viral load that was 0.4 log10 higher than undiluted samples. CONCLUSIONS/SIGNIFICANCE: The method of semen collection is an important consideration when quantifying the HIV RNA viral load in this compartment.