Simulated cost-effectiveness and long-term clinical outcomes of addiction care and antibiotic therapy strategies for patients with injection drug use-associated infective endocarditis

Importance: Emerging evidence supports the use of outpatient parenteral antimicrobial therapy (OPAT) and, in many cases, partial oral antibiotic therapy for the treatment of injection drug use-associated infective endocarditis (IDU-IE); however, long-term outcomes and cost-effectiveness remain unknown. Objective: To compare the added value of inpatient addiction care services and the cost-effectiveness and clinical outcomes of alternative antibiotic treatment strategies for patients with IDU-IE. Design, Setting, and Participants: This decision analytical modeling study used a validated microsimulation model to compare antibiotic treatment strategies for patients with IDU-IE. Model inputs were derived from clinical trials and observational cohort studies. The model included all patients with injection opioid drug use (N = 5 million) in the US who were eligible to receive OPAT either in the home or at a postacute care facility. Costs were annually discounted at 3%. Cost-effectiveness was evaluated from a health care sector perspective over a lifetime starting in 2020. Probabilistic sensitivity, scenario, and threshold analyses were performed to address uncertainty. Interventions: The model simulated 4 treatment strategies: (1) 4 to 6 weeks of inpatient intravenous (IV) antibiotic therapy along with opioid detoxification (usual care strategy), (2) 4 to 6 weeks of inpatient IV antibiotic therapy along with inpatient addiction care services that offered medication for opioid use disorder (usual care/addiction care strategy), (3) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by OPAT (OPAT strategy), and (4) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by partial oral antibiotic therapy (partial oral antibiotic strategy). Main Outcomes and Measures: Mean percentage of patients completing treatment for IDU-IE, deaths associated with IDU-IE, life expectancy (measured in life-years [LYs]), mean cost per person, and incremental cost-effectiveness ratios (ICERs). Results: All modeled scenarios were initialized with 5 million individuals (mean age, 42 years; range, 18-64 years; 70% male) who had a history of injection opioid drug use. The usual care strategy resulted in 18.63 LYs at a cost of $416 570 per person, with 77.6$412 150 per person. Compared with the OPAT strategy, the partial oral antibiotic strategy had an ICER of $163 370 per LY. Increasing IDU-IE treatment uptake and decreasing treatment discontinuation made the partial oral antibiotic strategy more cost-effective compared with the OPAT strategy. When assuming that all patients with IDU-IE were eligible to receive partial oral antibiotic therapy, the strategy was cost-saving and resulted in 0.0247 additional discounted LYs. When treatment discontinuation was decreased from 3.30$100 000 per LY threshold. Conclusions and Relevance: In this decision analytical modeling study, incorporation of OPAT or partial oral antibiotic approaches along with addiction care services for the treatment of patients with IDU-IE was associated with increases in the number of people completing treatment, decreases in mortality, and savings in cost compared with the usual care strategy of providing inpatient IV antibiotic therapy alone

Linkage Group Selection: Towards Identifying Genes Controlling Strain Specific Protective Immunity in Malaria

Protective immunity against blood infections of malaria is partly specific to the genotype, or strain, of the parasites. The target antigens of Strain Specific Protective Immunity are expected, therefore, to be antigenically and genetically distinct in different lines of parasite. Here we describe the use of a genetic approach, Linkage Group Selection, to locate the target(s) of Strain Specific Protective Immunity in the rodent malaria parasite Plasmodium chabaudi chabaudi. In a previous such analysis using the progeny of a genetic cross between P. c. chabaudi lines AS-pyr1 and CB, a location on P. c. chabaudi chromosome 8 containing the gene for merozoite surface protein-1, a known candidate antigen for Strain Specific Protective Immunity, was strongly selected. P. c. chabaudi apical membrane antigen-1, another candidate for Strain Specific Protective Immunity, could not have been evaluated in this cross as AS-pyr1 and CB are identical within the cell surface domain of this protein. Here we use Linkage Group Selection analysis of Strain Specific Protective Immunity in a cross between P. c. chabaudi lines CB-pyr10 and AJ, in which merozoite surface protein-1 and apical membrane antigen-1 are both genetically distinct. In this analysis strain specific immune selection acted strongly on the region of P. c. chabaudi chromosome 8 encoding merozoite surface protein-1 and, less strongly, on the P. c. chabaudi chromosome 9 region encoding apical membrane antigen-1. The evidence from these two independent studies indicates that Strain Specific Protective Immunity in P. c. chabaudi in mice is mainly determined by a narrow region of the P. c. chabaudi genome containing the gene for the P. c. chabaudi merozoite surface protein-1 protein. Other regions, including that containing the gene for P. c. chabaudi apical membrane antigen-1, may be more weakly associated with Strain Specific Protective Immunity in these parasites

Monoclonal auto-antibodies and sera of autoimmune patients react with Plasmodium falciparum and inhibit its in vitro growth

The relationship between autoimmunity and malaria is not well understood. To determine whether autoimmune responses have a protective role during malaria, we studied the pattern of reactivity to plasmodial antigens of sera from 93 patients with 14 different autoimmune diseases (AID) who were not previously exposed to malaria. Sera from patients with 13 different AID reacted against Plasmodium falciparum by indirect fluorescent antibody test with frequencies varying from 33-100%. In addition, sera from 37 AID patients were tested for reactivity against Plasmodium yoelii 17XNL and the asexual blood stage forms of three different P. falciparum strains. In general, the frequency of reactive sera was higher against young trophozoites than schizonts (p < 0.05 for 2 strains), indicating that the antigenic determinants targeted by the tested AID sera might be more highly expressed by the former stage. The ability of monoclonal auto-antibodies (auto-Ab) to inhibit P. falciparum growth in vitro was also tested. Thirteen of the 18 monoclonal auto-Ab tested (72%), but none of the control monoclonal antibodies, inhibited parasite growth, in some cases by greater than 40%. We conclude that autoimmune responses mediated by auto-Ab may present anti-plasmodial activity

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century