Kinetics of emergence of liver complications in hepatitis C virus infected patients and advanced fibrosis, with and without HIV-coinfection, after sustained virological response.

OBJECTIVE: There is scarce available evidence on the distribution over time of liver complications emergence in hepatitis C virus (HCV)-infected patients who achieve sustained virological response (SVR) with direct-acting antiviral (DAA)-based therapy. Therefore, we aimed at describing the kinetics of liver-related events appearance in this setting. DESIGN: A multicentric prospective cohort study. METHODS: HCV-monoinfected and HIV/HCV-coinfected patients from GEHEP-011 cohort, whose inclusion criteria were had achieved SVR with DAA-based therapy; liver stiffness prior to starting treatment at least 9.5 kPa; and available liver stiffness measurement at SVR. SVR was considered as the baseline time-point. RESULTS: One thousand and thirty-five patients were included, 664 (64%) coinfected with HIV. Before DAA-based therapy, 63 (6.1%) individuals showed decompensated cirrhosis. After SVR, 51 (4.9%) patients developed liver complications. Median (Q1-Q3) time to the emergence of hepatic events was hepatic encephalopathy 11 (7-24) months, ascites 14 (6-29) months, hepatocellular carcinoma (HCC) 17 (11-42) months and portal hypertension gastrointestinal bleeding (PHGB) 28 (22-38) months (P = 0.152). We define two profiles of liver complications: those emerging earlier (encephalopathy and ascites) and, those occurring continuously during the follow-up (HCC, PHGB) [median (Q1-Q3) time to emergence 12.7 (6.6-28.2) months vs. 25.4 (12.5-41.53) months, respectively (P = 0.026)]. CONCLUSION: The vast majority of HCV-infected patients who develop liver complications after reaching SVR with DAA do it within 3 years after SVR time-point. Specifically, hepatic encephalopathy and ascites do not usually emerge after this period. Conversely, HCC and PHGB may occur in longer term. It is critical to identify patients at risk of developing hepatic events to continue performing surveillance for them.

Negative Clinical Evolution in COVID-19 Patients Is Frequently Accompanied With an Increased Proportion of Undifferentiated Th Cells and a Strong Underrepresentation of the Th1 Subset.

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-19.

Genetic diversity of HIV in seminal plasma remains higher than in blood after short-term antiretroviral therapy.

OBJECTIVE: To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART). PATIENTS AND METHODS: Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIV env genetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity. RESULTS: Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2-5)) was lower than in the seminal compartment (median 6, (IQR 4-8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1-4.5)) than in blood (median 1 (IQR 1-1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). CONCLUSION: We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasma.

ART is key to clearing oncogenic HPV genotypes (HR-HPV) in anal mucosa of HIV-positive MSM.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is one of the most frequent non-AIDS-defining neoplasias in HIV patients, mainly in MSM, and it has been associated with chronic infection with high-risk human papilloma virus (HR-HPV). Our main objective was to determine HR-HPV clearance and acquisition rates and related factors and their relationship with the incidence of HSILs and ASCC in anal mucosa of HIV+ MSM. PATIENTS AND METHODS: The study included consecutive HIV-infected MSM between May 2010 and December 2018. Data were gathered at baseline and annually on their sexual behavior, CD4 and CD8 levels, plasma HIV viral load, and results of anal cytology, HPV PCR, and high-resolution anoscopy. RESULTS: Out of the 405 patients studied, 34.9% of patients cleared oncogenic genotypes (IQR: 37-69) within 49 months, and 42.9% acquired new genotypes within 36 months (IQR:12-60). In multivariate analysis, clearance was only significantly influenced by the duration of antiretroviral therapy (ART) (OR: 1.016, 95% CI 1.003-1.030). The incidence of HSILs was 30.86/1,000 patient-years and that of ASCC was 81.22/100,000 patient-years; these incidences were not influenced by the acquisition (acquired: 14.9% vs. non-acquired: 10.4%; p = 0.238) or clearance (cleared 11.4% vs. non-cleared: 13.2%; p = 0.662) rates of these viruses. CONCLUSIONS: The duration of ART appears to positively affect oncogenic genotype clearance in the anal mucosa of HIV+ MSM, although this clearance does not affect the incidence of HSILs or ASCC. The reduction in HSIL+ rate observed in our patients may be attributable to the bundle of measures adopted at our center.

Incidence of lymphoma in HIV-HCV-infected patients. Modifications in function of the anti-hepatitis C virus therapy.

The change in the incidence of lymphomas in function of the presence or absence of sustained virological response after anti-hepatitis C therapy in a cohort of human immunodeficiency (HIV)-hepatitis C (HCV) viruses coinfected patients was analyzed. A prospective cohort of 755 HIV-HCV coinfected patients who received their first anti-HCV therapy, based on interferon + ribavirin schemas, was evaluated. Incidence and histologic types of lymphomas were analyzed in two periods: (1) before administration of anti-HCV therapy and (2) after anti-HCV therapy. The association between lymphoma incidence and demographic, HIV- (minimum CD4+ cell count and CD4+ cell count at diagnosis of lymphoma, antiretroviral therapy, maximal HIV load and HIV load at diagnosis of lymphoma) and HCV-related variables (HCV load, genotype, sustained viral response to anti-HCV therapy) were analyzed. A total of 13 lymphomas [incidence rate (95% confidence interval), 0.72 (0.33-1.11) × 1000 person-years, time from HIV diagnosis to lymphoma diagnosis (median, interquartile range), 15 (11-19) years] were diagnosed. Nine of them were non-Hodgkin and four Hodgkin lymphomas. The median CD4+ T cell count at diagnosis of lymphoma was 457/mm3, with only two cases with values lower than 200/mm3. The incidence rate of non-Hodgkin lymphomas was similar pre- and post-anti HCV therapy [0.33 (0.00-0.65) vs 0.68 (0.08-1.26) × 1000 person-years, respectively, p > 0.05]. Patients with sustained virologic HCV response showed similar incidence rate of lymphomas than that of those without anti-HCV response. In conclusion, anti-HCV therapy does not modify the incidence rate of lymphomas in HIV-HCV coinfected patients.

Antiretroviral therapy as a factor protective against anal dysplasia in HIV-infected males who have sex with males.

OBJECTIVES: Chronic infection with oncogenic HPV genotype is associated with the development of anal dysplasia. Antiretroviral therapy (ART) has been shown to decrease the incidence of cervical carcinoma in women with HIV. We sought to: 1) describe the prevalence and grade of anal dysplasia and HPV infection in our study subjects; 2) analyze the grade of correlation between anal cytology, PCR of high-risk HPV, and histology; 3) identify the factors associated with the appearance of ≥ AIN2 lesions. DESIGN: Cross-sectional, prospective study. METHODS: A cohort of HIV-positive males (n = 140, mean age  = 37 years) who have sex with males (MSM) had epidemiological, clinical and analytical data collected. Anal mucosa samples were taken for cytology, HPV PCR genotyping, and anoscopy for histological analysis. RESULTS: Within the cohort, 77.1% were being treated with ART, 8.5% anoscopy findings were AIN2, and 11.4% carcinoma in situ; 74.2% had high-risk (HR), 59.7% low-risk (LR) HPV genotypes and 46.8% had both. The combination of cytology with PCR identifying HR-HPV better predicts the histology findings than either of these factors alone. Logistic regression highlighted ART as a protective factor against ≥ AIN2 lesions (OR: 0.214; 95%CI: 0.054-0.84). Anal/genital condylomas (OR: 4.26; 95%CI: 1.27-14.3), and HPV68 genotype (OR: 10.6; 95%CI: 1.23-91.47) were identified as risk factors. CONCLUSIONS: In our cohort, ART has a protective effect against dysplastic anal lesions. Anal/genital warts and HPV68 genotype are predictors of ≥ AIN2 lesions. Introducing PCR HPV genotype evaluation improves screening success over that of cytology alone.