To validate the accuracy of previously published US seroprevalence estimates for hepatitis D virus (HDV) antibody, we retested National Health and Nutrition Examination Survey samples from 2007‒2018 using a different assay. We found the HDV seroprevalence among hepatitis B surface antigen positive participants aged ≥6 years to be 1.26%.

BACKGROUND & AIMS:We evaluated the impact of hepatitis C virus (HCV) treatment adherence support among people who inject drugs (PWID) in India using a precision trial design. METHODS:Treatment-naïve participants with a history of injection drug use were recruited from community-based clinics across seven cities. All received sofosbuvir/velpatasvir once daily for 12 weeks. Failure risk was defined a priori using a prognostic score including age, sex, income, homelessness, injection frequency, depressive symptoms, quality of life indicators and sexual partners. Participants at elevated risk were randomized 3:2:1 to high- (patient navigator [PN]+flexible directly observed therapy [≥1 dose/week observed]), medium- (PN contact ≥every 2 weeks) or low-intensity support. Those at minimal risk were randomized 1:2:3 to high-, medium-, and low-intensity support. The primary outcome was sustained virologic response (SVR; HCV RNA <LLOQ 24 weeks post-randomization; intention to treat). RESULTS:A total of 3,000 participants were randomized between January 2021 and December 2022 (2,048 minimal risk and 952 elevated risk), and 2,798 (93.3%) completed SVR assessment. Among minimal-risk participants, SVR was 62.6%, 60.8%, and 68.3% with low-, medium-, and high-intensity support, respectively. Among elevated-risk participants, SVR was 48.4%, 45.5%, and 50.8%, respectively. Fifty-one participants experienced a serious adverse event, including 35 deaths. Among minimal-risk participants, high-intensity support was superior to low-intensity support (adjusted relative risk [aRR] 1.09; 95% CI 1.00-1.19; p = 0.04), whereas medium-intensity support was not (aRR 0.97; 95% CI 0.90-1.05). Among elevated-risk participants, neither low-intensity (aRR 0.96; 95% CI 0.80-1.15) nor medium-intensity (aRR 0.89; 95% CI 0.77-1.04) support differed from high-intensity support. Each 10% decrease in prognostic score was associated with a 6% increase in the likelihood of SVR (aRR 1.06; 95% CI 1.04-1.08). CONCLUSIONS:Prognostic scores could help target adherence interventions more efficiently; however, more intensive adherence support and/or novel interventions are needed to improve SVR among those at highest predicted risk. IMPACT AND IMPLICATIONS:This study is one of the largest hepatitis C treatment trials conducted to date. Our findings show that currently available adherence support interventions have limited impact on sustained virologic response among community-based people who inject drugs, indicating that more intensive or alternative strategies will be needed to achieve hepatitis C elimination in this population. At the same time, the findings provide strong evidence that prognostic scores can be used to target adherence interventions more efficiently in both clinical trials and routine care, particularly where resources are limited. CLINICAL TRIAL NUMBER:ClinicalTrials.gov NCT04652804.

PURPOSEHepatocellular carcinoma (HCC) is common and deadly in sub-Saharan Africa, where advanced imaging techniques, such as computerized tomography and magnetic resonance imaging, are scarce. The purpose of this study was to develop a pragmatic HCC diagnostic strategy for such settings.METHODSWe evaluated standardized protocol-collected data on clinical, ultrasonographic, biochemical, and pathological criteria in a multisite study of 649 suspected HCC cases in Uganda. Participants underwent standardized interviews, clinical assessments, and ultrasound examinations by trained staff with alpha-fetoprotein (AFP) testing at a central laboratory, and pathology was obtained for selected participants. Concordance analysis and percentage-confirmed yield using different HCC case definitions were performed, with survival follow-up as a validation measure.RESULTSThe median age was 45 years, 68% were male, and 45% had chronic hepatitis B infection. Ultrasonographic, biochemical (AFP), and pathological definitions confirmed 91%, 57%, and 17% of clinically defined HCC cases, respectively. The median survival after diagnosis was 46 days. An integrated HCC case definition that combined clinical criteria with one confirmatory test increased the percentage-confirmed yield by 3.7% (ultrasonographic), 37.7% (biochemical), and 77.7% (pathologic) over the clinical definition alone. Yield from AFP or pathology beyond ultrasound was minimal. Survival did not differ appreciably by HCC case definition. This integrated HCC case definition maintained diagnostic rigor while maximizing yield.CONCLUSIONWe propose an integrated HCC case definition as a pragmatic, resource-adaptable approach for clinical diagnosis and research in sub-Saharan Africa. This definition can be readily implemented and can support regional collaborative efforts to develop novel diagnostics and improved treatments to ameliorate the heavy HCC burden.

Although previous modelling work indicates treatment of < 10 people who inject drugs (PWID) per 100 person-years (PY) could achieve hepatitis C virus (HCV) elimination targets in many settings, these models frequently make simplifying assumptions of heterogeneity in infection risk. Here, we evaluated the impact of incorporating risk heterogeneity in transmission models on the predicted effects of interventions and the feasibility of HCV elimination in high-burden settings. We built an individual-based model of HCV transmission informed by detailed data from a cohort of PWID in Baltimore, MD, including an individual- and time-varying risk multiplier on the force of infection. We contrasted these risk-informed models to risk-agnostic models, ignoring this heterogeneity, and explored various levels of treatment and harm reduction scale-up from 2020 to 2030. Risk-agnostic models routinely estimated greater reductions in incidence (8%-19% higher for treatment rates of 10-90 per 100 PY) and greater numbers of infections averted per treatment course compared to otherwise equivalent populations modelled with risk heterogeneity. Elimination targets were only achieved in risk-informed models when treating 90 PWID per 100 PY. Expanding harm reduction services dramatically improved the impact of elimination programs, particularly in averting new infections soon after treatment scale-up initiation. Achieving HCV elimination targets among PWID in high-burden settings will require substantial improvements in treatment access and harm reduction services. Models that ignore the unequal distribution of HCV risk, including the correlation between reinfection risk and onward transmission, can result in inappropriately optimistic estimates of the feasibility of elimination.

The burden of hepatitis C virus (HCV) among persons who inject drugs is determined by dynamics of infection, spontaneous clearance, treatment clearance, treatment failure, and reinfection. We used deep sequencing by Nanopore to study sequences of persons with and without self-reported HCV treatment. Even after years of evolution, sequences from the same person were always more similar than sequences from different persons and a Hamming distance threshold of 0.064 reliably differentiated (AUC 0.999) the groups. By comparison to sequences before treatment, identification of unique sequences (distance > 0.064) after treatment reliably identified 8 of 28 instances of post-treatment reinfection. There were multiple causes for finding the same (distance < 0.064) sequence after intended treatment including not commencing or abbreviating treatment, pharmacological treatment failure, or possibly reinfection from same source. These data underscore the value of HCV sequence analysis in understanding viral dynamics among PWID.

Efforts to eliminate the hepatitis C virus (HCV) as a public health problem must include people who inject drugs (PWID). We describe the design and baseline characteristics of the Supporting Treatment Outcomes among PWID trial, which evaluates whether HCV treatment outcomes in PWID can be optimized by tailoring treatment support in 7 PWID-focused integrated HIV/HCV prevention/treatment centers across India. The design is a 3-arm, individual-level precision-randomized trial. Leveraging empirical data, a prediction model assigned participants as minimal or elevated risk for failure. Minimal-risk participants were randomized 3:2:1 to low-intensity (basic services), medium-intensity (patient navigation), and high-intensity (patient navigation + directly observed therapy) support, respectively. Elevated-risk participants were randomized 3:2:1 to high-, medium-, and low-intensity support, respectively. All received 12 weeks of oral direct-acting antiviral therapy. The primary outcome is sustained virologic response 12 weeks after treatment completion in an intention-to-treat analysis. Three thousand participants were randomized (2048 [68%] minimal risk, 952 [32%] elevated risk of failure). This approach will allow for the estimation of efficacy within treatment failure risk strata while preserving the ability to estimate the average treatment effect and has particular relevance with increasing emphasis on precision medicine in health care delivery. Trial registration: Identifier: NCT04652804.

Metagenomic next generation metagenomic sequencing (mNGS) has proven to be a useful tool in the diagnosis and identification of novel human pathogens and pathogens not identified on routine clinical microbiologic tests. In this study, we applied mNGS to characterize plasma RNA isolated from 42 study participants with unexplained acute febrile illness (AFI) admitted to tertiary referral hospitals in Mubende and Arua, Uganda. Study participants were selected based on clinical criteria suggestive of viral infection (i.e., thrombocytopenia, leukopenia). The study population had a median age of 28 years (IQR:24 to 38.5) and median platelet count of 114 x103 cells/mm3 (IQR:66,500 to 189,800). An average of 25 million 100 bp reads were generated per sample. We identified strong signals from diverse virus, bacteria, fungi, or parasites in 10 (23.8%) of the study participants. These included well recognized pathogens like Helicobacter pylori, human herpes virus-8, Plasmodium falciparum, Neisseria gonorrhoeae, and Rickettsia conorii. We further confirmed Rickettsia conorii infection, the cause of Mediterranean Spotted Fever (MSF), using PCR assays and Sanger sequencing. mNGS was a useful addition for detection of otherwise undetected pathogens and well-recognized non-pathogens. This is the first report to describe the molecular confirmation of a hospitalized case of MSF in sub-Saharan Africa (SSA). Further studies are needed to determine the utility of mNGS for disease surveillance in similar settings.

Nearly 300 million individuals live with chronic hepatitis B virus (HBV) infection (CHB), for which no curative therapy is available. As viral diversity is associated with pathogenesis and immunological control of infection, improved methods to characterize this diversity could aid drug development efforts. Conventionally, viral sequencing data are mapped/aligned to a reference genome, and only the aligned sequences are retained for analysis. Thus, reference selection is critical, yet selecting the most representative reference a priori remains difficult. We investigate an alternative pangenome approach which can combine multiple reference sequences into a graph which can be used during alignment. Using simulated short-read sequencing data generated from publicly available HBV genomes and real sequencing data from an individual living with CHB, we demonstrate alignment to a phylogenetically representative ‘genome graph’ can improve alignment, avoid issues of reference ambiguity, and facilitate the construction of sample-specific consensus sequences more genetically similar to the individual’s infection. Graph-based methods can, therefore, improve efforts to characterize the genetics of viral pathogens, including HBV, and have broader implications in host-pathogen research.

Abstract Background Efforts are underway to support the development of novel mucosal coronavirus disease 2019 (COVID-19) vaccines. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how to evaluate immunogenicity of mucosal vaccines. This study investigated the role of oral mucosal antibody responses in viral clearance and COVID-19 symptom duration. Methods Participants with polymerase chain reaction (PCR)–confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for reverse-transcription PCR, and symptom information at up to 8 follow-ups from April 2020 to February 2022. Results High and moderate oral fluid anti-spike (S) secretory IgA (SIgA) postinfection was associated with significantly faster viral clearance and symptom resolution across age groups with effect sizes equivalent to prior COVID-19 vaccine immunity at the time of infection. Those with high and moderate anti-S SIgA cleared the virus 14 (95% confidence interval [CI], 10–18) days and recovered 9–10 (95% CI, 6–14) days earlier. Delayed and higher anti-S IgG was associated with significantly longer time to clearance and recovery. Experiencing symptoms >4 weeks was associated with lower anti–receptor-binding domain SIgA 15–30 days after infection onset (P < .001). Conclusions Robust mucosal SIgA early postinfection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new mucosal vaccines.

The top 20 highest burdened countries (in disability-adjusted life years) account for more than 75% of the global burden of viral hepatitis. An effective response in these 20 countries is crucial if global elimination targets are to be achieved. In this update of the Lancet Gastroenterology & Hepatology Commission on accelerating the elimination of viral hepatitis, we convene national experts from each of the top 20 highest burdened countries to provide an update on progress. Although the global burden of diseases is falling, progress towards elimination varies greatly by country. By use of a hepatitis elimination policy index conceived as part of the 2019 Commission, we measure countries' progress towards elimination. Progress in elimination policy has been made in 14 of 20 countries with the highest burden since 2018, with the most substantial gains observed in Bangladesh, India, Indonesia, Japan, and Russia. Most improvements are attributable to the publication of formalised national action plans for the elimination of viral hepatitis, provision of publicly funded screening programmes, and government subsidisation of antiviral treatments. Key themes that emerged from discussion between national commissioners from the highest burdened countries build on the original recommendations to accelerate the global elimination of viral hepatitis. These themes include the need for simplified models of care, improved access to appropriate diagnostics, financing initiatives, and rapid implementation of lessons from the COVID-19 pandemic.

Orthopoxvirus-specific T-cell responses were analyzed in 10 patients who had recovered from Mpox including 7 people with human immunodeficiency virus (PWH). Eight participants had detectable virus-specific T-cell responses, including a PWH who was not on antiretroviral therapy and a PWH on immunosuppressive therapy. These 2 participants had robust polyfunctional CD4+ T-cell responses to peptides from the 121L vaccinia virus (VACV) protein. T-cells from 4 of 5 HLA-A2-positive participants targeted at least 1 previously described HLA-A2-restricted VACV epitope, including an epitope targeted in 2 participants. These results advance our understanding of immunity in convalescent Mpox patients.

The design of a clinical trial for a controlled human infection model (CHIM) to accelerate hepatitis C virus (HCV) vaccine development requires careful consideration. The design of a potential approach to HCV CHIM is outlined, involving initial sentinel cohorts to establish the safety and curability of the viral inoculum followed by larger cohorts to establish the spontaneous clearance rate for each inoculum. The primary endpoint would be HCV clearance by 24 weeks post-inoculation, recognizing that the prevention of chronic infection would be the primary goal of HCV vaccine candidates. Additional considerations are discussed, including the populations to be enrolled, the required monitoring approach, indications for antiviral therapy, and the required sample size for different CHIM approaches. Finally, safety considerations for CHIM participants are discussed.