Could late-latent syphilis be treated with a single subcutaneous infusion of long-acting penicillin?

Syphilis is an important global health threat and little has changed in its treatment since the mid-20th century. For late-latent or syphilis infection of unknown duration, the standard treatment of multiple intramuscular injections of benzathine penicillin G (BPG) are associated with significant pain and distress to clients and caregivers, negatively impacting on treatment completion. Based on pharmacokinetic modelling from a Phase I study of subcutaneous infusion of high dose BPG (SCIP), we present its feasibility, safety and tolerability for treatment of syphilis in a single infusion. SCIP leads to more sustained penicillin concentrations above the desired target with less reported pain and reduced clinic visits.

Clinical practice guidelines: Their utility, dissemination and monitoring at Colonial War Memorial Hospital: A mixed methods study from Fiji.

BACKGROUND: Clinical practice guidelines (CPGs) improve patient care by standardising medical practice. However, little is known about their applicability in low-resource settings. Since 2010, Fiji has introduced guidelines to increase the application of evidence-based practice. AIMS: We describe the dissemination, utility and monitoring of guideline implementation in Fiji, a low-resource setting in the Pacific. METHODS: A mixed-methods design included a survey and focus groups. All 178 doctors in five departments at Fiji's largest tertiary hospital were invited to participate. Subsequently, two focus group interviews explored clinicians' perspectives in more detail. Analysis included data description, multi-variable logistic, multinomial regression and manifest content analyses. RESULTS: The response rate was 74%. Most doctors agreed that CPGs were good for patient management (100%), doctors continuing medical education (CME) (96%), patient education (73%), supported by systematic reviews (91%) and consistent with existing norms/values (83%). Ninety-five per cent stated that CPGs increased the quality of care, and 80% stated that CPGs increased physician satisfaction. Approximately two-thirds stated that CPGs decreased medical-legal problems (63%) and malpractice suits (68%). Sixty to 90% of doctors disagreed that CPGs were oversimplified/cookbook medicine (60%), too rigid to apply individually (65%), challenged physician autonomy (60%) or were ambiguous/unclear (86%) or not practical (89%). The preferred method of dissemination was CME, and quick reference guides were best for implementation. No formal CPG monitoring existed in any department. CONCLUSION: Most physicians found CPGs to be valuable for improving the consistency of care. In low-resource settings, dissemination of guidelines should be paired with CME to improve their uptake. Increased monitoring of guideline use appears necessary.

2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease.

Rheumatic heart disease (RHD) is an important and preventable cause of morbidity and mortality among children and young adults in low-income and middle-income countries, as well as among certain at-risk populations living in high-income countries. The 2012 World Heart Federation echocardiographic criteria provided a standardized approach for the identification of RHD and facilitated an improvement in early case detection. The 2012 criteria were used to define disease burden in numerous epidemiological studies, but researchers and clinicians have since highlighted limitations that have prompted a revision. In this updated version of the guidelines, we incorporate evidence from a scoping review, an expert panel and end-user feedback and present an approach for active case finding for RHD, including the use of screening and confirmatory criteria. These guidelines also introduce a new stage-based classification for RHD to identify the risk of disease progression. They describe the latest evidence and recommendations on population-based echocardiographic active case finding and risk stratification. Secondary antibiotic prophylaxis, echocardiography equipment and task sharing for RHD active case finding are also discussed. These World Heart Federation 2023 guidelines provide a concise and updated resource for clinical and research applications in RHD-endemic regions.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

A single dose of quadrivalent HPV vaccine is highly effective against HPV genotypes 16 and 18 detection in young pregnant women eight years following vaccination: an retrospective cohort study in Fiji.

Background: In 2008/9, Fiji vaccinated >30,000 girls aged 9-12 years with the quadrivalent human papillomavirus (4vHPV) vaccine coverage for at least one dose was >60% (one dose only was 14%, two dose only was 13%, three doses was 35%). We calculated vaccine effectiveness (VE) of one, two and three doses of 4vHPV against oncogenic HPV genotypes 16/18, eight years following vaccination. Methods: A retrospective cohort study was undertaken (2015-2019) in pregnant women ≤23 years old, eligible to receive 4vHPV in 2008/9, with confirmed vaccination status. The study was restricted to pregnant women due to the cultural sensitivity of asking about sexual behavior in Fiji. For each participant a clinician collected a questionnaire, vaginal swab and genital warts examination, a median eight (range 6-11) years post vaccination. HPV DNA was detected by molecular methods. Adjusted VE (aVE) against the detection of vaccine HPV genotypes (16/18), the comparison group of non-vaccine genotypes (31/33/35/39/45/51/52/56/58/59/66/68), and genital warts were calculated. Covariates included in the adjusted model were: age, ethnicity and smoking, according to univariate association with any HPV detection. Findings: Among 822 participants the prevalence of HPV 16/18 in the unvaccinated, one, two and three-dose groups were 13.3% (50/376), 2.5% (4/158), 0% (0/99) and 1.6% (3/189), respectively; and for the non-vaccine high-risk genotypes, the detection rate was similar across dosage groups (33.2%-40.4%, p = 0.321). The aVE against HPV 16/18 for one, two and three doses were 81% (95% CI; 48-93%), 100% (95% CI; 100-100%), and 89% (95% CI; 64-96%), respectively. Prevalence of HPV 16/18 was lower among women with longer time since vaccination. Interpretations: A single dose 4vHPV vaccine is highly effective against HPV genotypes 16 and 18 eight years following vaccination. Our results provide the longest duration of protection for reduced dose 4vHPV schedule in a low- or middle-income country in the Western Pacific region. Funding: This study was supported by the Bill & Melinda Gates Foundation and the Department of Foreign Affairs and Trade of the Australian Government and Fiji Health Sector Support Program (FHSSP). FHSSP is implemented by Abt JTA on behalf of the Australian Government.

Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease.

BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

Population-based assessment of cardiovascular complications of rheumatic heart disease in Fiji: a record-linkage analysis.

OBJECTIVE: To determine population-based rates of non-fatal complications of rheumatic heart disease (RHD). DESIGN: Retrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage. SETTING: Fiji, an upper-middle-income country, where most of the population has access to government-funded healthcare services. PARTICIPANTS: National cohort of 2116 patients with clinically apparent RHD aged 5-69 years during 2008 and 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator. RESULTS: Among 2116 patients in the national cohort (median age, 23.3 years; 57.7% women), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0-40 years (heart failure, 210/454, 46.3%; ischaemic stroke 31/134, 23.1%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared with men (incidence rate ratio 1.4, 95% CI 1.3 to 1.6, p<0.001). Hospitalisation for any RHD complication was associated with substantially increased risk of death (HR 5.4, 95% CI 3.4 to 8.8, p<0.001), especially after the onset of heart failure (HR 6.6, 95% CI 4.8 to 9.1, p<0.001). CONCLUSIONS: Our study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low-income and middle-income countries worldwide. Hospitalisation for an RHD complication is associated with markedly increased risk of death, re-emphasising the importance of effective early prevention.

Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.

INTRODUCTION: Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)-the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). METHODS: Participants (n = 24) received between 6.9 mL to 20.7 mL (3-9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. RESULTS: Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. CONCLUSION: Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

Prevention of bacterial complications of scabies using mass drug administration: A population-based, before-after trial in Fiji, 2018-2020.

Background: Scabies is an important predisposing factor of impetigo which can lead to serious bacterial complications. Ivermectin-based mass drug administration can substantially reduce scabies and impetigo prevalence in endemic settings, but the impact on serious bacterial complications is not known. Methods: We conducted a before-after trial in the Northern Division of Fiji (population: 131,914) of mass drug administration for scabies control. Prospective surveillance was conducted from 2018 to 2020. Mass drug administration took place in 2019, involving two doses of oral ivermectin or topical permethrin, delivered alongside diethylcarbamazine and albendazole for lymphatic filariasis. The primary outcomes were incidence of hospitalisations with skin and soft tissue infections, and childhood invasive infections and post-streptococcal sequelae. Secondary outcomes included presentations to primary healthcare with skin infections and community prevalence of scabies and impetigo. Findings: The incidence of hospitalisations with skin and soft tissue infections was 17% lower after the intervention compared to baseline (388 vs 467 per 100,000 person-years; incidence rate ratio 0.83, 95% CI, 0.74 to 0.94; P = 0.002). There was no difference in incidence of childhood invasive infections and post-streptococcal sequelae. Incidence of primary healthcare presentations with scabies and skin infections was 21% lower (89.2 vs 108 per 1000 person-years, incidence rate ratio, IRR 0.79, 95% CI, 0.78 to 0.82). Crude community prevalence of scabies declined from 14.2% to 7.7% (cluster-adjusted prevalence 12.5% to 8.9%; prevalence ratio 0.71, 95% CI, 0.28 to 1.17). Cluster-adjusted prevalence of impetigo declined from 15.3% to 6.1% (prevalence ratio 0.4, 95% CI, 0.18 to 0.86). Interpretation: Mass drug administration for scabies control was associated with a substantial reduction in hospitalisations for skin and soft tissue infections. Funding: National Health and Medical Research Council of Australia and Scobie and Claire Mackinnon Trust.

Costs of mass drug administration for scabies in Fiji.

In 2019, the Murdoch Children's Research Institute in partnership with the Fiji Ministry of Health and Medical Services carried out an integrated mass drug administration (MDA) for the treatment of scabies and lymphatic filariasis in the Northern Division of Fiji (population estimate 131,914). We conducted a retrospective micro-costing exercise focused on the cost of scabies control in order to inform budgeting and policy decision making in an endemic setting. We collected detailed information on financial and economic costs incurred by both parties during the course of the MDA campaign (April 2018 to July 2019). We also conducted interviews with personnel involved in the financial administration of the MDA campaign. The economic cost of delivering two doses of ivermectin was US$4.88 per person. The cost of donated drugs accounted for 36.3% of total MDA costs. In this first large-scale MDA for the public health control of scabies, the estimated cost of delivering MDA per person for scabies was considerably more expensive than the costs reported for other neglected tropical diseases. The important cost drivers included the remuneration of health care workers who were extensively involved in the campaign, coverage of hard-to-reach, mainly rural populations and the two-dose regimen of ivermectin. These results highlight the importance of these cost determinants and can be used to plan current and future MDA programs.

Study protocol for controlled human infection for penicillin G against Streptococcus pyogenes: a double-blinded, placebo-controlled, randomised trial to determine the minimum concentration required to prevent experimental pharyngitis (the CHIPS trial).

INTRODUCTION: Regular intramuscular benzathine penicillin G injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. As the pharmacological correlate of protection remains unknown, it is difficult to recommend changes to this established regimen. Determining the minimum effective penicillin exposure required to prevent Streptococcus pyogenes infection will accelerate development of new long-acting penicillins for RHD prevention as well as inform opportunities to improve existing regimens. The CHIPS trial will address this knowledge gap by directly testing protection afforded by different steady state plasma concentrations of penicillin in an established model of experimental human S. pyogenes pharyngitis. METHODS AND ANALYSIS: This is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18-40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous penicillin infusions targeting five different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. Each participant's penicillin pharmacokinetic parameters will be established prior to the challenge, to ensure accurate dosing for the continuous infusion. Following the challenge with a well-characterised strain of S. pyogenes, participants will be observed for up to 6 days for the development of pharyngitis and treated with antibiotics prior to discharge. The primary objective is to determine the minimum effective steady-state plasma penicillin concentration required to prevent experimental pharyngitis. Secondary objectives will explore systemic and mucosal immunoinflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination and qualitative evaluation of the participant experience. ETHICS AND DISSEMINATION: Ethical approval has been obtained (Bellberry Human Research Ethics Committee). Findings will be reported in peer-reviewed publications and presented at national/international stakeholder forums. TRIAL REGISTRATION NUMBER: ACTRN12621000751875.

Prospective Surveillance of Primary Healthcare Presentations for Scabies and Bacterial Skin Infections in Fiji, 2018-2019.

Scabies, impetigo, and other skin and soft tissue infections (SSTIs) are highly prevalent in many tropical, low-middle income settings, but information regarding their burden of disease is scarce. We conducted surveillance of presentations of scabies and SSTIs, including impetigo, abscesses, cellulitis, and severe SSTI, to primary health facilities in Fiji. We established a monthly reporting system over the course of 50 weeks (July 2018-June 2019) for scabies and SSTIs at all 42 public primary health facilities in the Northern Division of Fiji (population, ≈131,914). For each case, information was collected regarding demographics, diagnosis, and treatment. There were 13,736 individual primary healthcare presentations with scabies, SSTI, or both (108.3 presentations per 1000 person-years; 95% confidence interval [CI], 106.6-110 presentations). The incidence was higher for males than for females (incidence rate ratio [IRR], 1.15; 95% CI, 1.11-1.19). Children younger than 5 years had the highest incidence among all age groups (339.1 per 1000 person-years). The incidence was higher among the iTaukei (indigenous) population (159.9 per 1000 person-years) compared with Fijians of Indian descent (30.1 per 1000 person-years; IRR, 5.32; 95% CI, 5.03-5.61). Abscess was the condition with the highest incidence (63.5 per 1,000 person-years), followed by scabies (28.7 per 1,000 person-years) and impetigo (21.6 per 1,000 person-years). Scabies and SSTIs impose a substantial burden in Fiji and represent a high incidence of primary health presentations in this population. The incidence in low-middle income settings is up to 10-times higher than that in high-income settings. New public health strategies and further research are needed to address these conditions.

Prospective surveillance for invasive Staphylococcus aureus and group A Streptococcus infections in a setting with high community burden of scabies and impetigo.

BACKGROUND: Invasive Staphylococcus aureus (iSA) and group A Streptococcus (iGAS) impose significant health burdens globally. Both bacteria commonly cause skin and soft tissue infections (SSTIs), which can result in invasive disease. Understanding of the incidence of iSA and iGAS remains limited in settings with a high SSTI burden. METHODS: Prospective surveillance for admissions with iSA or iGAS was conducted at the referral hospital in Fiji's Northern Division over 48 weeks between July 2018 and June 2019. RESULTS: There were 55 admissions for iSA and 15 admissions for iGAS (incidence 45.2 and 12.3 per 100,000 person-years, respectively). The highest incidence was found in patients aged ≥65 years (59.6 per 100,000 person-years for iSA and iGAS). The incidence of iSA was higher in indigenous Fijians (iTaukei) (71.1 per 100,000 person-years) compared with other ethnicities (incidence rate ratio 9.7, 95% confidence interval 3.5-36.9). SSTIs were found in the majority of cases of iSA (75%) and iGAS (53.3%). Thirteen of the 14 iGAS strains isolated belonged to emm cluster D (n = 5) or E (n = 8). The case fatality rate was high for both iSA (10.9%) and iGAS (33.3%). CONCLUSIONS: The incidence of iSA and iGAS in Fiji is very high. SSTIs are common clinical foci for both iSA and iGAS. Both iSA and iGAS carry a substantial risk of death. Improved control strategies are needed to reduce the burden of iSA and iGAS in Fiji.

Hospital admissions for skin and soft tissue infections in a population with endemic scabies: A prospective study in Fiji, 2018-2019.

Scabies is an important predisposing factor for impetigo but its role in more serious skin and soft tissue infections (SSTIs) is not well understood. Information is limited on incidence of SSTIs in the presence of endemic scabies. We conducted a prospective study of hospital admissions for SSTIs in the Northern Division of Fiji (population: 131,914). Prospective surveillance for admissions with impetigo, abscess, cellulitis, wound infection, pyomyositis, necrotizing fasciitis, infected scabies, and crusted scabies was conducted at the Division's referral hospital between 2018 to 2019. Information was collected on demographic characteristics, clinical features, microbiology, treatment and outcomes. Over the study period, 788 SSTI admissions were recorded corresponding to a population incidence 647 per 100,000 person-years (95%CI 571-660). Incidence was highest at the extremes of age with peak incidence in children aged <5 years (908 per 100,000) and those aged ≥65 years (1127 per 100,000). Incidence was 1.7 times higher among the Indigenous Fijian population (753 per 100,000) compared to other ethnicities (442 per 100,000). Overall case fatality rate was 3.3%, and 10.8% for those aged ≥65 years. Scabies was diagnosed concurrently in 7.6% of all patients and in 24.6% of admitted children <5 years. There is a very high burden of hospital admissions for SSTIs in Fiji compared to high-income settings especially among the youngest, oldest and indigenous population which is concordant with scabies and impetigo distribution in this population. Our findings highlight the need for strategies to reduce the burden of SSTIs in Fiji and similar settings.

The American Heart Association's Call to Action for Reducing the Global Burden of Rheumatic Heart Disease: A Policy Statement From the American Heart Association.

Rheumatic heart disease (RHD) affects ≈40 million people and claims nearly 300 000 lives each year. The historic passing of a World Health Assembly resolution on RHD in 2018 now mandates a coordinated global response. The American Heart Association is committed to serving as a global champion and leader in RHD care and prevention. Here, we pledge support in 5 key areas: (1) professional healthcare worker education and training, (2) technical support for the implementation of evidence-based strategies for rheumatic fever/RHD prevention, (3) access to essential medications and technologies, (4) research, and (5) advocacy to increase global awareness, resources, and capacity for RHD control. In bolstering the efforts of the American Heart Association to combat RHD, we hope to inspire others to collaborate, communicate, and contribute.

Subcutaneous administration of benzathine benzylpenicillin G has favourable pharmacokinetic characteristics for the prevention of rheumatic heart disease compared with intramuscular injection: a randomized, crossover, population pharmacokinetic study in healthy adult volunteers.

BACKGROUND: Benzathine penicillin G has been used as monthly deep intramuscular (IM) injections since the 1950s for secondary prevention of acute rheumatic fever and rheumatic heart disease (RHD). Injection frequency and pain are major programmatic barriers for adherence, prompting calls for development of better long-acting penicillin preparations to prevent RHD. We hypothesized that subcutaneous (SC) administration of benzathine penicillin G could delay penicillin absorption when compared with IM injections. METHODS: To compare the pharmacokinetic profile and tolerability of benzathine penicillin G according to different routes of administration, 15 healthy males participated in a randomized crossover study to receive benzathine penicillin G by either SC or IM routes, with a 10 week washout period before the second dose by the alternative route. Ultrasound guidance confirmed injection location. Penicillin concentrations and pain scores were measured for 6 weeks following injections. RESULTS: SC administration was well tolerated with no significant differences in pain scores. Following SC injection, the principal absorption half-life (95% CI) was 20.1 (16.3-29.5) days and 89.6% (87.1%-92.0%) of the drug was directed via this pathway compared with 10.2 (8.6-12.5) days and 71.3% (64.9%-77.4%) following IM administration. Lower peak and higher trough penicillin concentrations resulted following SC injection. Simulations demonstrated that SC infusion of higher doses of benzathine penicillin G could provide therapeutic penicillin concentrations for 3 months. CONCLUSIONS: SC administration of benzathine penicillin G is safe and significantly delays penicillin absorption. High-dose benzathine penicillin G via the SC route would fulfil many product characteristics required for the next generation of longer-acting penicillins for use in RHD.

The Human Leukocyte Antigen Locus and Rheumatic Heart Disease Susceptibility in South Asians and Europeans.

Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P = 3.48×10-10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.

The cost-of-illness due to rheumatic heart disease: national estimates for Fiji.

BACKGROUND: Rheumatic heart disease (RHD) is a chronic valvular heart disease that is responsible for a heavy burden of premature mortality in low- and middle-income countries. The total costs of RHD are important to health policy and research investment decisions. We estimate for the first time the total cost of RHD for Fiji (2008-2012) using a cost-of-illness approach and novel primary data on RHD disease burden and costs. METHODS: RHD cases were identified using probabilistic record linkage across four routine data sources: (1) the Fiji RHD Control Program, (2) national hospital admissions records, (3) the Ministry of Health database of cause-specific deaths and (4) hospital ECG clinic registers. For each individual with RHD, we obtained information on RHD hospital admissions, treatment and death. We conducted a prevalence-based cost-of-illness analysis, including bottom-up assessment of indirect and direct (healthcare) costs. RESULTS: The estimated cost of RHD in Fiji for 2008-2012 was year-2010 $FJ91.6 million (approximately US$47.7 million). Productivity losses from premature mortality constituted the majority of costs (71.4%). Indirect costs were 27-fold larger than the direct costs. CONCLUSIONS: RHD leads to a heavy economic burden in Fiji. Improved prevention strategies for RHD will likely confer substantial economic benefits to the country.