Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1. METHODS: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791. FINDINGS: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per µL) and total lymphocyte counts (mean change -0·20 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Circulating HBV RNA and hepatitis B core-related antigen trajectories in persons with HIV/HBV coinfection and HBsAg loss on tenofovir therapy.

BACKGROUND: We evaluated long-term trajectories of circulating hepatitis B virus (HBV)-RNA and hepatitis B core-related antigen (HBcrAg) in persons with and without hepatitis B surface antigen (HBsAg) loss during tenofovir therapy in the Swiss HIV Cohort Study. METHODS: We included 29 persons with HIV (PWH) with HBsAg loss and 29 matched PWH without loss. We compared HBV-RNA and HBcrAg decline and assessed the cumulative proportions with undetectable HBV-RNA and HBcrAg levels during tenofovir therapy using Kaplan-Meier estimates. RESULTS: HBsAg loss occurred after a median of 4 years (IQR 1 - 8). All participants with HBsAg loss achieved suppressed HBV-DNA and undetectable HBV-RNA preceding undetectable qHBsAg levels, whereas 79% achieved negative HBcrAg. In comparison, 79% of the participants without HBsAg loss achieved undetectable HBV-RNA and 48% negative HBcrAg. After two years on tenofovir, an HBV RNA decline ≥1 log10 copies/ml had 100% sensitivity and 36.4% specificity for HBsAg loss, whereas an HBcrAg decline ≥1 log10 U/ml had 91.0% sensitivity and 64.5% specificity. CONCLUSIONS: HBV-RNA suppression preceded undetectable qHBsAg levels, and had high sensitivity but low specificity for HBsAg loss during tenofovir therapy in PWH. HBcrAg remained detectable in approximately 20% of persons with, and 50% of persons without HBsAg loss.

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N  = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

Long-term quantitative hepatitis B surface antigen (HBsAg) trajectories in persons with and without HBsAg loss on tenofovir-containing antiretroviral therapy.

OBJECTIVES: Improving the understanding of the patterns of quantitative hepatitis B surface antigen (qHBsAg) trajectories associated with HBsAg loss is important in light of novel anti-hepatitis B virus agents being developed. We evaluated long-term qHBsAg trajectories in persons with HIV and HBV during tenofovir-containing antiretroviral therapy in the Swiss HIV Cohort Study. METHODS: We included 29 participants with and 29 without HBsAg loss, defined as qHBsAg <0.05 IU/mL. We assessed qHBsAg decline during therapy in both groups and used agglomerative hierarchical clustering to identify different qHBsAg trajectory profiles in persons with HBsAg loss. RESULTS: The median follow-up time was 11.9 years (IQR 8.4-14.1), and the median time to HBsAg loss was 48 months (IQR 12-96). Among participants with HBsAg loss, 79% had a qHBsAg decline ≥1 log10 IU/mL 2 years after starting tenofovir. The trajectories in qHBsAg levels during tenofovir therapy were heterogeneous, characterized by five distinct profiles. Among participants without HBsAg loss, only 7% had a qHBsAg decline ≥1 log10 IU/ml after 2 years. CONCLUSIONS: Most persons with HIV who experienced HBsAg loss had an early decline in qHBsAg levels, with diverse trajectories during long-term tenofovir therapy. In persons without HBsAg loss, qHBsAg levels remained remarkably stable over time.

Early combination therapy of COVID-19 in high-risk patients.

PURPOSE: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect. METHODS: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 106 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed. RESULTS: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 106 copies/ml of 8.0 days (IQR 6.0-15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2-9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment. CONCLUSION: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

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.

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.

Sexual and drug use risk behaviour trajectories among people treated for recent HCV infection: the REACT study.

INTRODUCTION: Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection. METHODS: Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation. RESULTS: During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories. CONCLUSIONS: Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment.

Reinfection incidence and risk among people treated for recent hepatitis C virus infection.

OBJECTIVE: Reinfection poses a challenge to hepatitis C virus (HCV) elimination. This analysis assessed incidence of, and factors associated with reinfection among people treated for recent HCV (duration of infection <12 months). METHODS: Participants treated for recent HCV (primary infection or reinfection) in an international randomized trial were followed at 3-monthly intervals for up to 2 years to assess for reinfection. Reinfection incidence was calculated using person-time of observation. Factors associated with HCV reinfection were assessed using Cox proportional hazards regression analysis. RESULTS: Of 222 participants treated for recent HCV, 196 (62% primary infection, 38% reinfection) were included in the cohort at risk for reinfection, of whom 87% identified as gay or bisexual men, 71% had HIV and 20% injected drugs in the month prior to enrolment. During 198 person-years of follow-up, 28 cases of HCV reinfection were identified among 27 participants, for an incidence of 14.2 per 100 person-years [95% confidence interval (CI) 9.8-20.5]. Reinfection was associated with prior HCV reinfection [adjusted hazards ratio (aHR) 2.42; 95% CI 1.08-5.38], injection drug use posttreatment (aHR 2.53; 95% CI 1.14-5.59), condomless anal intercourse with casual male partners (aHR 3.32; 95% CI 1.14-9.65) and geographic region (United Kingdom, aHR 0.21; 95% CI 0.06-0.75). Among gay and bisexual men (GBM), reinfection was also associated with sexualized drug use involving injecting posttreatment (aHR 2.97; 95% CI 1.10-8.02). CONCLUSION: High reinfection incidence following treatment for recent HCV among people with ongoing sexual and drug use risk behaviour highlights the need for posttreatment surveillance, rapid retreatment of reinfection and targeted harm reduction strategies.

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.

Impact of hepatitis C cure on risk of mortality and morbidity in people with HIV after antiretroviral therapy initiation.

OBJECTIVE: Hepatitis C virus (HCV) co-infection is associated with increased morbidity and mortality in people with HIV (PWH). Sustained virological response (SVR) decreases the risk of HCV-associated morbidity. We compared mortality, risk of AIDS-defining events, and non-AIDS nonliver (NANL) cancers between HCV-co-infected PWH who reached SVR and mono-infected PWH. DESIGN: Adult PWH from 21 cohorts in Europe and North America that collected HCV treatment data were eligible if they were HCV-free at the time of ART initiation. METHODS: Up to 10 mono-infected PWH were matched (on age, sex, date of ART start, HIV acquisition route, and being followed at the time of SVR) to each HCV-co-infected PWH who reached SVR. Cox models were used to estimate relative hazards (hazard ratio) of all-cause mortality, AIDS-defining events, and NANL cancers after adjustment. RESULTS: Among 62 495 PWH, 2756 acquired HCV, of whom 649 reached SVR. For 582 of these, at least one mono-infected PWH could be matched, producing a total of 5062 mono-infected PWH. The estimated hazard ratios comparing HCV-co-infected PWH who reached SVR with mono-infected PWH were 0.29 [95% confidence interval (CI) 0.12-0.73] for mortality, 0.85 [0.42-1.74] for AIDS-defining events, and 1.21 [0.86-1.72] for NANL cancer. CONCLUSION: PWH who reached SVR a short time after HCV acquisition were not at higher risk of overall mortality compared with mono-infected PWH. However, the apparent higher risk of NANL cancers in HCV-co-infected PWH who reached SVR after a DAA-based treatment compared with mono-infected PWH, though compatible with a null association, suggests a need for monitoring of those events following SVR.

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.

External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection.

BACKGROUND & AIMS: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. METHODS: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. RESULTS: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10-17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03-3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. CONCLUSIONS: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. IMPACT AND IMPLICATIONS: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.

Hepatitis delta infection among persons living with HIV in Europe.

BACKGROUND AND AIMS: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. METHODS: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression. RESULTS: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0). CONCLUSION: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence.

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.

Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study).

BACKGROUND: Using direct-acting antivirals (DAAs) for recently acquired hepatitis C virus (RAHCV) infections, particularly in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), dramatically reduced the incidence of hepatitis C. However, implementation into clinical practice is challenging. The aim of this study was to analyze spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC. METHODS: The PROBE-C study is an observational European cohort on RAHCV infections in HIV-positive MSM. Between 2007 and 2017, RAHCV infections were documented with ≥12 months of follow-up. Fisher exact, χ2, and Mann-Whitney U tests were used for statistical analysis. RESULTS: A total of 464 RAHCV infections were documented; 457 of 464 patients (98%) were male, and the median age (interquartile range [IQR]) was 41 (38-46) years. The main risk group for hepatitis C virus (HCV) transmission was MSM (98.9%). Most participants were infected with HCV genotype 1 (78.3%). The median baseline HCV RNA level (IQR) was 230 000 (135 000-474 432) IU/mL, and the median CD4+ T-cell count was 574/µL (547-604/µL. Of all cases, 92% received combination antiretroviral therapy, with 91% showing suppressed HIV RNA levels (<200 copies/mL). The median maximum alanine aminotransferase level (IQR) was 445 (402-522) U/L. SC of RAHCV infection occurred in 55 of 464 cases (11.9%). A >2-log decline in HCV RNA levels 4 weeks after diagnosis of RAHCV infection was the strongest predictor of SC (P < .001; sensitivity, 96.4%; specificity, 97.5%; positive predictive value, 84.1%; negative predictive value, 99.5%). CONCLUSIONS: SC of RAHCV in HIV-positive MSM is found in only 11.9% of cases and a <2-log drop in HCV RNA level at week 4 after diagnosis should prompt early DAA-based treatment. However, immediate DAA treatment for RAHCV infection may also be favored in patients with ongoing transmission risk behavior.