The research section of the Toolkit provides summaries of recent publications from a variety of scientific, peer-reviewed journals that document findings associated with the lopinavir/ritonavir (LPV/r) pellet formulation since 2014. Links to the associated abstract or full-text publication are also provided. The research section of the Toolkit is updated quarterly.
Giralt, A.N., Nöstlinger, C., Lee, J., et al. BMJ Open (March 2017), 7(3): e014528, doi: 10.1136/bmjopen-2016-014528.
This paper described the protocol of the RE-LIVING study, a sub-study within the LIVING study. LIVING (2015–2019) is a Phase III, single-arm trial that is currently field-testing a "child-friendly" pellet formulation of lopinavir/ritonavir (LPV-r) for children living with HIV in three settings in Kenya. The RE-LIVING sub-study will conduct a "realist" evaluation of context-specific factors influencing adherence to and acceptability of the 40mg/10mg pellet formulation--specifically, caregivers' correct administration of the pellets and their continued adherence to administering the pellets over the long term. Caregiver-infant pairs who have been enrolled in the LIVING study and transitioned from syrup to pellets will be included. The researchers will collect data from multiple sources: LIVING study outcomes; in-depth interviews with caregivers, providers, and health managers; and users' experiences in terms of administering the pellets, support for adherence, and client-provider interactions, including communication abilities. Purposive sampling at each site will include 15 caregiver interviews, 5 provider or manager interviews, and to one or two provider focus group discussions. The study will also include observations of users' experiences with the pellets in clinical and home settings. The study's findings will contribute to the knowledge base on adherence in general, and will provide new data on caregivers' views of and adherence to this pellet-based formulation in pediatric patients.
Musiime, V., Fillekes, Q., Kekitiinwa, A., et al. Journal of Acquired Immune Deficiency Syndrome (June 2014), 66: 148–154.
This article summarized the CHAPAS-2 trial in Uganda, which compared the lopinavir/ritonavir (LPV/r) mini-tab sprinkle formulation to LPV/r syrup among 77 children aged 3–12 months, 1–4 years, and 4–13 years. Children were started on sprinkles, syrup, or tablets, and switched to an alternative formulation, depending on age, after 8 weeks. Children aged 3–12 months and 1–4 years had slightly higher LPV/r concentrations (but still comparable) when taking the sprinkles in contrast to the syrup. Children aged 4–12 years had slightly higher blood concentrations when taking LPV/r tablets versus sprinkles. Among younger children in the cohorts for ages aged 3–12 months and 1–4 years, more challenges were associated with taking the syrup than the sprinkles. Among children aged 4–12 years, more challenges were associated with taking the sprinkles than the tablets. For all formulations, the most commonly reported challenge was taste; the syrup tasted worse than the sprinkles, and the sprinkles tasted worse than tablets. Among children aged 3–12 months, the syrup was reported to be more challenging than sprinkles to swallow (60% versus 20%). Children aged 1–4 reported the sprinkles as more difficult than syrup to swallow (27% versus 19%). Children aged 4–12 did not report any difficulties swallowing tablets; but 13 percent reported challenges swallowing sprinkles. After 8 weeks, around three-quarters of caregivers of children aged 3–12 months and 1–4 years opted to continue with sprinkles versus syrup; only 22 percent of caregivers of children aged 4–12 years opted to continue sprinkles versus tablets. Among the younger groups, caregivers preferred sprinkles, reporting that they were easier to administer, transport, and store. The authors concluded that for countries following World Health Organization guidance to use LPV/r as first-line therapy, LPV/r sprinkles are an acceptable alternative to syrup.
Wilhelm, A., Amole, C., Middlecote, C., et al. 21st International AIDS Conference Abstract Supplement, Journal of the International AIDS Society (2016), 19 (Suppl 5), doi: 10.7448/IAS.19.6.21264.
This abstract summarized findings on the country-level cost of adopting the 2015 World Health Organization (WHO) guidance, including providing universal pediatric HIV treatment for all children under 15 years old. The costing study used costs associated with using lopinavir/ritonavir (LPV/r) pellets instead of syrup in children under 3 years of age. The authors made a five-year calculation, assuming a pediatric HIV burden of 150,000 children, and compared the costs of using WHO 2013 versus 2015 guidelines (treating children under 5 years old and all older children with a CD4 count <500 versus universal treatment of all children under 15 years). The findings showed that in the year 2016, reaching 90 percent coverage would cost USD$116 per patient for the 2013 guidance versus $122 per patient for the 2015 guidance. In 2020, costs would be $152 versus $156 for the 2013 and 2015 guidance, respectively. Implementation of LPV/r pellets only added an additional $4 million to five-year costs. There was a 23 percent increase in overall costs using 2015 World Health Organization guidelines including LPV/r pellets. The authors concluded that this information can help countries to plan for implementation of the WHO guidelines including use of the pellets
View full PPT [PPT, 472KB]
Kekitiinwa, A., Musiime, V., Thomason, M.J, et al. Antiretroviral Therapy (2016); 21:579–585, doi: 10.3851/IMP3054.
This article described the acceptability of lopinavir/ritonavir (LPV/r) pellets in infants and children between 3 months and 13 years old enrolled in the Pharmacokinetics and Adherence of Simple ARV Regimens, or CHAPAS-2, trial. This trial compared LPV/r syrup, tablets, and pellets in two Ugandan clinics. The findings showed that preference for the pellets increased between enrollment and 12 weeks among of caregivers with children aged 1–4 years; after 12 weeks, caregivers' preference for the pellets declined. For caregivers of older children, pellet preference steadily decreased over time. At week 48, preference was higher in one clinic than the other for pellets than for other formulations among caregivers of children aged 1–4 and 4–13. Similar numbers of caregivers of infants and children aged 1–4 reported that both the syrup and the pellets had an unpleasant taste. Among older children, pellets were reported to have a worse taste than tablets. Caregivers reported more challenges with transport and storage for the syrup than the pellets. Children 1–4 years old also experienced more challenges swallowing the syrup than the pellets. Caregivers who preferred the syrup stated that the pellets had a bitter taste, and that they had difficulty hiding the taste in other foods and liquids, and often resorted to buying expensive honey or sugar to do so. They also voiced concerns that the child might not be receiving the full dose. For breastfed infants, mothers generally reported that giving pellets with breastmilk was easy. Among children who had a viral load taken at 48 weeks, all had a viral load below 1000 copies/ml. The authors concluded that countries following World Health Organization guidance and prescribing LPV/r as first-line treatment should take the LPV/r formulation under consideration.
6th edition (March 2017).
This document outlines technical specifications justifying inclusion of lopinavir/ritonavir (LPV/r) in pellet form within the WHO (World Health Organization) Model List of Essential Medicines (EML). The dossier for LPV/r provides a summary statement from the manufacturer for inclusion of LPV/r in the EML for children. Information on public health relevance details disease burden epidemiology, an assessment of current usage of LPV/r pellets, and the target population for LPV/r usage. Treatment details include information on the current WHO treatment recommendations, including use of LPV/r, the recommended dosage regimen, and duration of use. The document provides a summary of the drug's comparative effectiveness in a variety of clinical settings, including details on the various LPV/r formulations for children and study outcomes from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1060 study and the Children with HIV in Africa - Pharmacokinetics and Adherence of Simple Antiretroviral Regimens, or CHAPAS-2 Trial. A summary of comparative evidence on safety details potential adverse effects, potential variations in safety due to health system- and patient-related factors, and drug interactions that may require a dosage adjustment. Summaries of comparative cost effectiveness for each form of LPV/r (including solution, pellet, and tablet) are provided, along with a summary of the regulatory status of pellets and availability of pharmacopeia standards.
Barlow-Mosha, L., Angelidou, K., Lindsey, L., et al. Clinical Infectious Diseases (July 2016), 63(8); 1113–11121, doi: 10.1093/cid/ciw488.
This five-year study examined the long-term effects of lopinavir/ritonavir (LPV/r) regimen versus nevirapine (NVP) in 451 children who had taken part in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study. IMPAACT P1060 had shown that in children under age three, the LPV/r regimen was associated with fewer treatment failures or deaths over 12 months, but growth and CD4 counts were somewhat better with NVP . Throughout the 60-month study, the proportion of children experiencing viral failure or death was 17 percent higher among those on the NVP-based regimen than the LPV/r-based regimen. Death was most likely to occur in the first 3–6 months of follow-up. Greater CD4 percent gains were noted among children on the NVP-based regimen, but these gains were not noted after 12 months of follow-up. Though the initial 4–6 months were a high–risk period for death among infants on NVP-based regimens, those who survived this period experienced similar virologic suppression rates as children on LPV/r-based regimens. The authors concluded that the pediatric LPV/r-based regimen was associated with fewer deaths than the NVP-based regimen. LPV/r-based regimens should be continued as first-line treatment. NVP-based regimens are a viable alternative if the LPV/r based regimen is not available.