Abstract Background Diagnostic test evaluation requires a reference standard. We describe an approach for creating a reference standard for acute infection using unrestricted adjudication and apply it to compare biomarker tools. Methods Adults and children with suspected acute infection enrolled in three prospective studies at emergency departments and urgent cares were included. Adjudicators, blinded to C-reactive protein, procalcitonin, and MeMed BV (MMBV), labeled each case (bacterial/viral/non-infectious/indeterminate). Initial adjudication involved 3 adjudicators. Reference standard cohorts were defined: Microbiologically confirmed (3/3 adjudicators concur with high confidence and a concordant microbiological finding), unanimous (3/3 adjudicators concur with high confidence), suspected (3/3 adjudicators concur with high/moderate confidence or 2/3 adjudicators concur with high confidence), and all-inclusive (remaining unlabeled cases were reviewed by up to 7 additional adjudicators until reaching a leading label). Results Among 1016 patients, 156 difficult-to-diagnose cases required over 3 adjudicators. The area under the receiver operating characteristic curve in the microbiologically confirmed (n = 427), unanimous (n = 565), suspected (n = 860), and all-inclusive (n = 1016) cohorts for MMBV were 0.98 (95% confidence interval .94–1.00), 0.98 (.95–1.00), 0.95 (.92–.98) and 0.90 (.87–.93), respectively, and for procalcitonin were 0.69 (.57–.81), 0.77 (.68–.86), 0.74 (.68–.80) and 0.70 (.65–.75), respectively. A delta in performance between MMBV and procalcitonin was maintained across the different cohorts. Conclusions Creating a reference standard that includes difficult-to-diagnose cases demands an approach to addressing diagnostic uncertainty in acute infections. Tool performance depends on the reference standard applied and decreases as the difficulty to diagnose increases, highlighting the importance of using the same reference standard when comparing tools.

Abstract Background The global mpox outbreak which started in May 2022 was caused by a novel clade IIb variant of the mpox virus (MPXV). It differed from the traditional Western and Central Africa disease in transmission patterns and clinical presentation. Methods To address the need for detailed clinical and virologic data, we conducted an observational cohort study (MOSAIC) during May 2022-July 2023 in individuals with confirmed MPXV infection enrolled in six European Countries. Case-management decisions were left to the attending physician. Participants were monitored for up to six months for clinical signs/symptoms and clinical and virologic outcomes through hospital visits, phone interviews, and self-administered questionnaires. Outcomes included time-to-lesion resolution, clinical status, and virus clearance. Results The 518 participants not receiving any specific treatment (“untreated”) were diagnosed a median 5 days from symptom onset; 90% were managed as outpatients. Lesions were mostly cutaneous (88%) as and peri-genital (74%). By Day 14 from the first PCR-positive sample, 39% had resolved lesions. Time-to 95% unculturable virus was longest in cutaneous lesions (52 days). A putative systemic antiviral was available for 57 participants, 44% as in-patients, 34% and 58% had resolved lesions by D14 from the first PCR-positive sample and from treatment start, respectively. Time-to 95% unculturable virus was 60 days in skin and oropharynx. No death or recrudescence occurred by Day 180. Conclusion MOSAIC provides comprehensive insights into the clinical and virologic characteristics of mpox caused by the clade IIb variant. The study forms the basis of clinical characterisation for ongoing mpox outbreaks.

Abstract Background Tenofovir-containing antiretroviral therapy (ART) improves survival in hepatitis B virus (HBV)–coinfected people with HIV (PWH). We investigated the incidence of hepatitis D virus (HDV) infection and its clinical impact in HBV-coinfected PWH in the era of tenofovir-containing ART. Methods Between 2011 and 2022, HBV-coinfected PWH were included and followed until December 2023. Anti-HDV antibody screening was performed using sequentially archived blood samples. Timing of incident HDV infection was estimated as the midpoint between the last timepoint of anti–HDV-negative samples and the first timepoint of anti–HDV-positive samples. Differences in survival and liver-related outcomes between HDV-infected and -uninfected PWH were analyzed. Results 534 HBV-coinfected PWH were included; 36 (6.7%) tested HDV-seropositive at baseline. During 3987.78 person-years of follow-up (PYFU), 50 (10.0%) of 498 anti–HDV-negative PWH seroconverted for HDV, with an overall incidence rate of 12.54 per 1000 PYFU; 88.0% (44/50) of HDV seroconverters were men who have sex with men. After a median follow-up of 10.2 years (84.7% of the follow-up period covered by tenofovir-containing ART), all-cause mortality was 4.7% (25/534). PWH with HDV had significantly higher rates of liver-related mortality (3.5% vs 0.4%, P = .032), cirrhosis (11.3% vs 3.6%, P = .008), and hepatitis flare (28.2% vs 14.2%, P = .001) than HDV-uninfected PWH. In multivariate Cox analysis, HDV infection was associated with liver-related mortality (adjusted HR, 9.696; 95% CI, 1.284–73.222, P = .028). Risk of hepatocellular carcinoma was similar for HDV-infected and HDV-uninfected PWH. Conclusions HBV-coinfected PWH remain at risk of HDV superinfection and HDV infection is associated with liver-related death in the era of tenofovir-containing ART.

Abstract Background Most research on human immunodeficiency virus-1 (HIV-1) viremia and cancer risk is from high-income countries. We evaluated the association between HIV-1 viremia and the risk of various cancer types among people with HIV (PWH) in South Africa. Methods We analyzed data from the South African HIV Cancer Match study, based on laboratory measurements from the National Health Laboratory Service and cancer records from the National Cancer Registry from 2004 to 2014. Using Cox proportional hazards models, we estimated hazard ratios (HR) for cancer incidence per unit increase in time-updated Log10 HIV-1 RNA viral load copies/mL. We created partially adjusted (sex, age, calendar year) and fully adjusted models (additionally including time-updated CD4 count). Results We included 2 770 200 PWH with 10 175 incident cancers; most common were cervical cancer (N = 2481), Kaposi sarcoma (N = 1902), breast cancer (N = 1063), and non-Hodgkin lymphoma (N = 863). Hazard ratios for the association of HIV-1 viremia and cancer risk changed after partial and full adjustment and were generally attenuated for infection-related cancers but tended to increase for infection-unrelated cancers. In the fully adjusted model, HIV-1 viremia was associated with an increased risk of Kaposi sarcoma (HR per unit increase in Log10 HIV-1 RNA viral load: 1.38; 95% confidence interval [CI], 1.35–1.42), leukemia (HR: 1.28; 95% CI, 1.13–1.45), non-Hodgkin lymphoma (HR: 1.24; 95% CI, 1.19–1.29), conjunctival cancer (HR: 1.19; 95% CI, 1.11–1.25), and colorectal cancer (HR: 1.11; 95% CI, 1.02–1.21). Associations with other cancer types were weaker or absent. Conclusions Our findings underline the importance of sustained viral suppression for cancer prevention among PWH in South Africa.

Abstract A distinction between infections of left ventricular assist devices (LVADs) and cardiac implantable electronic devices (CIEDs) is warranted as they differ markedly in incidence, microbiologic profiles, clinical presentations, and extraction feasibility. These differences necessitate tailored suppressive antibiotic therapy (SAT) strategies. This commentary highlights the need for device-specific SAT approaches.

Abstract Background This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). Methods A prospective cohort study was conducted on people with human immunodeficiency virus (HIV, PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB + RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma human immunodeficiency virus type 1 (HIV-1) viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. Results Among 173 patients with a median (interquartile range [IQR]) follow-up of 11.1(7.1–13.2) months and 789 pre-dose measurements, 38.7% experienced VL ≥ 20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in 2 cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis (adjusted hazard ratio [AHR]: 1.49 per log10 VL, 95% confidence interval [CI]: 1.04–2.12, P = .027), detectable viremia on oral ART (AHR: 2.45, 95% CI: 1.29–4.65, P = .006), and the level of viral suppression at transition (AHR: 0.38, 95% CI: .19–.75, P = .004). We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. Conclusions Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB + RPV LA was linked to preexisting factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.