HIV-Associated Microbial Translocation May Affect Cytokine Production of CD56bright NK Cells via Stimulation of Monocytes.

The mechanisms involved in HIV-associated natural killer (NK) cell impairment are still incompletely understood. We observed HIV infection to be associated with increased plasma levels of IFABP, a marker for gut epithelial barrier dysfunction, and LBP, a marker for microbial translocation. Both IFABP and LBP plasma concentrations were inversely correlated with NK cell interferon-γ production, suggesting microbial translocation to modulate NK cell functions. Accordingly, we found lipopolysaccharide to have an indirect inhibitory effect on NK cells via triggering monocytes' transforming growth factor-ß production. Taken together, our data suggest increased microbial translocation to be involved in HIV-associated NK cell dysfunction.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

BACKGROUND: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. KEY POINTS OF THE GUIDELINES UPDATE: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. CONCLUSIONS: In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.

People living with HIV, HCV and HIV/HCV coinfection in intensive care in a German tertiary referral center 2014-2019.

PURPOSE: The epidemiology of HIV-infected individuals on the Medical Intensive Care Units (MICU) has changed after profound progress in treatment of AIDS-defining illnesses and anti-retroviral therapy (ART). Changes of MICU utilization of Hepatitis C (HCV) patients following roll-out of direct-acting antivirals (DAA) are yet to evaluate. METHODS: We performed a retrospective study on all patients with HIV, HIV/HCV and HCV admitted to the MICU of University Hospital Bonn 2014-2019. We assessed sociodemographic data, available clinical data from HIV patients (CDC stage, CD4 + lymphocyte cell count, HIV-1-RNA, ART) and HCV patients (HCV-RNA, stage of liver cirrhosis, treatment history) and outcome. RESULTS: 237 patients (46 HIV, 22 HIV/HCV, 169 HCV; 168 male, median age 51.3 years) with 325 MICU admissions were included. Admission criteria for HIV patients were infections (39.7% AIDS-associated, 23.8% with controlled HIV-infection) and cardiopulmonary diseases (14.3%). HIV/HCV coinfected patients had infections in controlled/uncontrolled HIV-infection (46.4%), cardiopulmonary diseases and intoxication/drug abuse (17.9% each). Reasons for HCV-mono-infected patients were infections (24.4%), sequelae of liver disease (20.9%), intoxication/drug abuse (18.4%) and cardiopulmonary diseases (15%). 60 patients deceased; most important risk factor was need for mechanical ventilation. The number of HCV-patients admitted to MICU with chronic active disease and sequelae of liver disease decreased while the proportion of patients with completed DAA-treatment increased. CONCLUSION: Infections remain the most important reason for MICU admission in patients with HIV and/or HCV infection while non-AIDS related conditions increased. DAA roll-out has a beneficial effect on liver-associated morbidity in HCV patients admitted to MICU.

Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Against SARS-CoV-2 After Natural Infection Is More Potent Than After Vaccination.

We compared the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific antibodies to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 coronavirus disease 2019 (COVID-19) patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than 3 months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

Impact of COVID-19 on HIV late diagnosis in a specialized German centre.

BACKGROUND: The ongoing COVID-19 pandemic has been impeding HIV diagnosis and treatment worldwide. Data on the impact of COVID-19 on late diagnosis (LD) in Germany are lacking. Here we present novel data of a single-centre German HIV cohort assessing LD during COVID-19. METHODS: This is a non-interventional, single-centre retrospective cohort assessing the rate of LD comparing HIV diagnoses pre-COVID-19 with those during the COVID-19 pandemic. New diagnoses between 1 January 2019 and 1 February 2020 were classified as pre-COVID-19, and diagnoses between 1 February 2020 and 1 October 2021 were classified as during COVID-19. RESULTS: Between 1 January 2019 and 1 October 2021, 75 patients presented with newly diagnosed HIV infection, 34 pre-COVID-19 and 41 during COVID-19. LD increased to 83% (n = 34/41) during COVID-19 versus 59% (n = 20/34) pre-COVID-19, and CDC stage C3 rose to 44% (n = 18) versus 27%. Hospitalization rate increased to 49% (n = 20) during COVID-19 versus 29% pre-COVID-19, and 12% (n = 5) presented with HIV-associated neurological disease, whereas none were observed in the pre-COVID-19 group. The incidence of LD (p = 0.020), CD4 count < 350 cells/µL (p = 0.037) and < 200 cells/µL (p = 0.022) were statistically significantly associated with the ongoing COVID-pandemic. An association with HIV transmission risk was borderline significant (p = 0.055). CONCLUSIONS: Despite comparable annual rates of new HIV diagnoses, LD has been increasing during the COVID-19 pandemic, resulting in more opportunistic infections and higher hospitalization rates, possibly reflecting pandemic-related shortages in HIV testing and care facilities. Maintaining HIV testing opportunities and access to treatment during a pandemic is crucial so as not to impede WHO elimination goals and so as to prevent an increase in AIDS-related morbidity and mortality.

The association between hepatitis B virus infection and nonliver malignancies in persons living with HIV: results from the EuroSIDA study.

OBJECTIVES: The aim of this study was to assess the impact of hepatitis B virus (HBV) infection on non-liver malignancies in people living with HIV (PLWH). METHODS: All persons aged ≥ 18 years with known hepatitis B virus (HBV) surface antigen (HBsAg) status after the latest of 1 January 2001 and enrolment in the EuroSIDA cohort (baseline) were included in the study; persons were categorized as HBV positive or negative using the latest HBsAg test and followed to their first diagnosis of nonliver malignancy or their last visit. RESULTS: Of 17 485 PLWH included in the study, 1269 (7.2%) were HBV positive at baseline. During 151 766 person-years of follow-up (PYFU), there were 1298 nonliver malignancies, 1199 in those currently HBV negative [incidence rate (IR) 8.42/1000 PYFU; 95% confidence interval (CI) 7.94-8.90/1000 PYFU] and 99 in those HBV positive (IR 10.54/1000 PYFU; 95% CI 8.47-12.62/1000 PYFU). After adjustment for baseline confounders, there was a significantly increased incidence of nonliver malignancies in HBV-positive versus HBV-negative individuals [adjusted incidence rate ratio (aIRR) 1.23; 95% CI 1.00-1.51]. Compared to HBV-negative individuals, HBsAg-positive/HBV-DNA-positive individuals had significantly increased incidences of nonliver malignancies (aIRR 1.37; 95% CI 1.00-1.89) and NHL (aIRR 2.57; 95% CI 1.16-5.68). There was no significant association between HBV and lung or anal cancer. CONCLUSIONS: We found increased rates of nonliver malignancies in HBsAg-positive participants, the increases being most pronounced in those who were HBV DNA positive and for NHL. If confirmed, these results may have implications for increased cancer screening in HIV-positive subjects with chronic HBV infection.

Comparative Analysis of Antibody Titers against the Spike Protein of SARS-CoV-2 Variants in Infected Patient Cohorts and Diverse Vaccination Regimes.

The presence of neutralizing antibodies against SARS-CoV-2 correlates with protection against infection and severe COVID-19 disease courses. Understanding the dynamics of antibody development against the SARS-CoV-2 virus is important for recommendations on vaccination strategies and on control of the COVID-19 pandemic. This study investigates the dynamics and extent of α-Spike-Ab development by different vaccines manufactured by Johnson & Johnson, AstraZeneca, Pfizer-BioNTech and Moderna. On day 1 after vaccination, we observed a temporal low-grade inflammatory response. α-Spike-Ab titers were reduced after six months of vaccination with mRNA vaccines and increased 14 days after booster vaccinations to a maximum that exceeded titers from mild and critical COVID-19 and Long-COVID patients. Within the group of critical COVID-19 patients, we observed a trend for lower α-Spike-Ab titers in the group of patients who survived COVID-19. This trend accompanied higher numbers of pro-B cells, fewer mature B cells and a higher frequency of T follicular helper cells. Finally, we present data demonstrating that past infection with mild COVID-19 does not lead to long-term increased Ab titers and that even the group of previously infected SARS-CoV-2 patients benefit from a vaccination six months after the infection.

[HIV Test in Pregnancy - 100% Not Reached in 2020]. / HIV-Test in der Schwangerschaft ­ 2020 noch nicht bei 100.

INTRODUCTION: In 2019 38 million people were living with HIV worldwide, more than half of them girls and women. Knowledge about maternal HIV status enables HIV transmission prophylaxis, reducing mother-to-child transmission<1%. We aimed to investigate the implementation of the mandatory documentation of counseling and optional HIV testing in the maternity records as recommended in the German maternity guidelines. METHODS: In the Obstetric Department of the University Hospital Bonn, maternity records were reviewed from June to October 2020, and pregnant women were interviewed regarding the patients' recall of counseling and HIV testing as well as their attitude towards a universal screening strategy using an anonymous questionnaire. RESULTS: Documentation was incomplete in 11% of maternal records: in 8% there was neither documentation of counseling nor of HIV testing, in 3% documentation of counseling only. In 291 questionnaires 47% of pregnant women could not recall counselling. 90% of pregnant women were in favor of universal HIV testing in pregnancy, 9% were undecided, and 1% opposed it. 55% would support change from an "opt-in" to an "opt-out" screening policy in pregnancy. SUMMARY: Documentation of counseling and HIV testing was incomplete in 11% of cases, and nearly half of the women could not recall counselling. New strategies from midwives and obstetricians need to be developed to achieve universal HIV testing in pregnant women leading to zero HIV mother-to-child transmissions.

SARS-CoV-2 seroconversions and chains of infection in healthcare professionals in a German maximum care provider (The CoSHeP study).

INTRODUCTION: The CoSHeP study provides novel data on SARS-CoV-2 seroconversion rates in healthcare professionals (HP) at risk at the University Hospital Bonn, a maximum healthcare provider in a region of 900.000 inhabitants. METHODS: Single-center, longitudinal observational study investigating rate of SARS-CoV-2 IgG seroconversion in HP at 2 time-points. SARS-CoV-2 IgG was measured with Roche Elecsys Anti-SARS-CoV-2 assay. RESULTS: Overall, 150 HP were included. Median age was 35 (range: 19-68). Main operational areas were intensive care unit (53%, n = 80), emergency room (31%, n = 46), and infectious disease department (16%, n = 24). SARS-CoV-2-IgG was detected in 5 participants (3%) at inclusion in May/June 2020, and in another 11 participants at follow-up (December 2020/ January 2021). Of the 16 seropositive participants, 14 had already known their SARS-CoV-2 infection because they had performed a PCR-test previously triggered by symptoms. Trailing chains of infection by self-assessment, 31% (n = 5) of infections were acquired through private contacts, 25% (n = 4) most likely through semi-private contacts during work. 13% (n = 2) were assumed to result through contact with contagious patients, further trailing was unsuccessful in 31% (n = 5). All five participants positive for SARS-CoV-2 IgG at inclusion remained positive with a median of 7 months after infection. DISCUSSION: Frontline HP caring for hospitalized patients with COVID-19 are at higher risk of SARS-CoV-2 infections. Noteworthy, based upon identified chains of infection most of the infections were acquired in private environment and semi-private contacts during work. The low rate of infection through infectious patients reveals that professional hygiene standards are effective in preventing SARS-CoV-2 infections in HP. Persisting SARS-CoV-2-IgG might indicate longer lasting immunity supporting prioritization of negative HP for vaccination.

Obstacles to HBV functional cure: Late presentation in HIV and its impact on HBV seroconversion in HIV/HBV coinfection.

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates.

HIV Care in Ukrainian Migrants in Two European Countries: All the Same?

Introduction: War in Ukraine prompted an enormous refugee influx into Europe, including approximately 4200 people with HIV. The unique healthcare features of Ukrainian refugees living with HIV were compared between two infectious disease departments in Bonn, Germany, and Szczecin, Poland. Methods: This is a retrospective study on 161 people living with HIV (PLWH) refugees from Ukraine seeking care in Bonn (n = 30) and Szczecin (n = 131) between April 2022 and May 2023. Demographic, virologic, immunologic, and coinfection data were analyzed. Results: The majority of the studied individuals were female: 64% (n = 84) in Szczecin and 60% (n = 18) in Bonn. The main HIV transmission mode was heterosexual sex in 73.5% (n = 114). All were on combined antiretroviral therapy (cART) on arrival, primarily on the TLD regimen (TDF/3TC/DTG) (68.4%, n = 106). In Germany, cART was most frequently switched to BIC/TAF/FTC in 83.4% (n = 25); in Poland, the most common combination was TDF/FTC + DTG (58%, n = 76). A prevalence of replicating hepatitis C was in 11.7% (n = 15), and that for chronic hepatitis B (HBV) was in 4.7% (n = 4). History of past tuberculosis was reported in 16.9% (n = 14, Poland, and n = 7, Germany). Follow-up after 6 months showed immunological reconstitution with a mean increase of CD4+ of 10 (IQR: -69.5-120.5) cells/µL in Poland and 51.5 (IQR: -22.5-135.5) cells/µL in Germany; p = 0.04. Virologic suppression (<40 HIV-RNA/mL) was high in care entry (n = 62; 98%) for Poland, and n = 26 (92.6%) for Germany, and suppression was achieved in the majority of patients in the 6-month control (89.7% in Poland vs. 95.7% in Germany). Conclusions: Health challenges posed by war migration extend beyond HIV to coinfections as HBV, HCV, and tuberculosis give an indication for a broader search for coinfections, often less common in the new country.

Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients.

Introduction: Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment. Methods: In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented. Results: In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed. Conclusion: Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.

Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART).

BACKGROUND: De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD. METHODS: This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates. FINDINGS: 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m2 (OR: 4·238, 95% CI: 2·078-8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362-10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370-4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315-24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12-0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101-0·945; p = 0·04). INTERPRETATION: Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m2. While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis. FUNDING: There was no additional funding received for this project. All funders mentioned in the 'declaration of interests' section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.