Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.

BACKGROUND: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. METHODS: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. RESULTS: Of 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve 0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; C max 3.04 mg/L [0.03-18.6 mg/L]; C 8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve 24 121.63 mg/h/L [2.56-487.3 mg/h/L]; C max 9.45 mg/L [0.39-26.4 mg/L]; C 12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. CONCLUSIONS: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.

Prevalence of rheumatic heart disease in Zambian school children.

BACKGROUND: The large global burden of rheumatic heart disease (RHD) has come to light in recent years following robust epidemiologic studies. As an operational research component of a broad program aimed at primary and secondary prevention of RHD, we sought to determine the current prevalence of RHD in the country's capital, Lusaka, using a modern imaging-based screening methodology. In addition, we wished to evaluate the practicality of training local radiographers in echocardiography screening methods. METHODS: Echocardiography was conducted on a random sample of students in 15 schools utilizing a previously validated, abbreviated screening protocol. Through a task-shifting scheme, and in the spirit of capacity-building to enhance local diagnostic and research skills, general radiographers based at Lusaka University Teaching Hospital (UTH) were newly trained to use portable echocardiography devices. Students deemed as screen-positive were referred for comprehensive echocardiography and clinical examination at UTH. Cardiac abnormalities were classified according to standard World Heart Federation criteria. RESULTS: Of 1102 students that were consented and screened, 53 students were referred for confirmatory echocardiography. Three students had definite RHD, 10 had borderline RHD, 29 were normal, and 11 students were lost to follow-up. The rates of definite, borderline, and total RHD were 2.7 per 1000, 9.1 per 1000, and 11.8 per 1000, respectively. Anterior mitral valve leaflet thickening and chordal thickening were the most common morphological defects. The pairwise kappa test showed fair agreement between the local radiographers and an echocardiographer quality assurance specialist. CONCLUSION: The prevalence of asymptomatic RHD in urban communities in Zambia is within the range of results reported in other sub-Saharan African countries using the WHF criteria. Task-shifting local radiographers to conduct echocardiography was feasible. The results of this study will be used to inform ongoing efforts in Zambia to control and eventually eliminate RHD. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov ( #NCT02661763 ).

A programme to increase appropriate usage of benzathine penicillin for management of streptococcal pharyngitis and rheumatic heart disease in Zambia.

Rheumatic heart disease is highly prevalent and associated with substantial morbidity and mortality in many resource-poor areas of the world, including sub-Saharan Africa. Primary and secondary prophylaxis with penicillin has been shown to significantly improve outcomes and is recognised to be the standard of care, with intra-muscular benzathine penicillin G recommended as the preferred agent by many technical experts. However, ensuring compliance with therapy has proven to be challenging. As part of a public-private partnership initiative in Zambia, we conducted an educational and access-to-medicine programme aimed at increasing appropriate use of benzathine penicillin for the prevention and management of rheumatic heart disease, according to national guidelines. The programme was informed early on by identification of potential barriers to the administration of injectable penicillin, which included concern by health workers about allergic events. We describe this programme and report initial signs of success, as indicated by increased use of benzathine penicillin. We propose that a similar approach may have benefits in rheumatic heart disease programmes in other endemic regions.

Epidemiology of pharyngitis as reported by Zambian school children and their families: implications for demand-side interventions to prevent rheumatic heart disease.

BACKGROUND: Prompt and appropriate treatment of streptococcal pharyngitis decreases the risk of acute rheumatic fever and rheumatic heart disease (RHD). Understanding public perceptions and behaviors related to sore throat is fundamental to inform health programs aimed at eliminating new cases of RHD in endemic regions. We sought to describe the epidemiology of pediatric pharyngitis and its treatment, as reported by children and their parents or guardians in Lusaka, Zambia. METHODS: This was a cross-sectional investigation using interviews and written surveys, nested in a school-based RHD prevalence study. Students and their parents were asked to report number of sore throats in the previous 12 months, treatment received, and type and place of treatment. A focused history and physical examination to detect pharyngitis was conducted and children were referred for follow-up as indicated. RESULTS: A total of 3462 students from 47 schools participated in the study, along with their parents or guardians. Six hundred and fifty eight (19%) parents/guardians reported their child had at least one sore throat in the previous year, and 835 (24%) of students reported at least one sore throat in the same time period. Girls were reported to have pharyngitis 50% more often than boys, and also made up two-thirds of the total students treated. Approximately two-thirds of children who had at least one episode of pharyngitis during the previous year were also reported to have received some form of treatment. The majority of treatments were received in government clinics (36.6%) and at home (26.3%). Half of treatments included an antibiotic. Nineteen students (0.5%) had clinically-apparent pharyngitis at screening. CONCLUSION: Pharyngitis is common among school-aged children and adolescents in Zambia, with females reporting significantly more sore throat episodes than males. Parents/guardians have variable knowledge about the frequency of sore throat in their children, and management of pharyngitis may be suboptimal for many children since more than a quarter were reported to have received treatment without skilled assessment. These results provide insight into current perceptions and practices related to sore throat in Zambia and will be used to design public awareness activities aimed at reducing RHD.