Lopinavir/ritonavir (LPV/r) oral pellets and oral granules for infants and young children living with HIV have proven advantages in terms of efficacy and tolerability over other formulations of LPV/r, but uptake has been slow in low- and middle-income countries with the highest HIV burden, according to Dr Christine Y Malati and colleagues at the United States Agency for International Development, Washington, DC in a commentary.
They identified three challenges: limited manufacturing capacity; the current unit cost of pellets and granules; and the slow uptake of these new drug formulations by policy makers and healthcare workers.
Only 52% of children under 15 years living with HIV are on lifesaving antiretroviral therapies and in many cohorts rates of viral suppression are low. Without effective treatment half of children will die before their second birthday and only one in five will survive to five years of age. However, there is a paucity of paediatric treatment options.
Nevirapine is available as a syrup or tablets, but children on nevirapine-based regimens are twice as likely to have drug resistance and thus treatment failure as children on protease inhibitors, such as LPV/r.
While the integrase inhibitors, raltegravir and dolutegravir are recommended as preferred or alternative first-line antiretrovirals for paediatric use, notably raltegravir for neonates, they are currently not readily accessible due to cost, manufacturing capacity and other factors.
This means LPV/r-based regimens are the only available optimal first-line antiretrovirals for young infants and children in high-burden countries. LPV/r is available as oral solution, heat-stable tablets, oral pellets and oral granules.
Oral solution is required for infants under three months of age, but needs refrigeration and has an unpleasant taste. The tablets cannot be crushed, affecting correct dosage.
Oral pellets and granules are similar products, introduced in 2015 and 2018 by two different generic manufacturers. Although they are clinically equivalent and dosed at the same frequency, switching between the two products is not recommended.
Oral pellets and granules have several advantages over oral solution and heat-stable tablets, including being easier to provide at a range of doses, easier storage and improved taste. They are usually given to the child along with semi-solid food such as porridge or yoghurt, or a liquid such as water or breast milk.
Nonetheless, uptake of the newer LPV/r formulations is significantly lower than expected. The authors focus on oral pellets due to more experience with pellets compared to granules.
Challenges and recommendations
1) Limited manufacturing capacity
The relatively small (and decreasing) number of patients eligible for paediatric formulations negatively affects the market. The introduction of LPV/r oral pellets into routine paediatric treatment means demand is outstripping supply. Effective rollout is limited primarily because Cipla and Mylan are the only two manufacturers with approval to manufacture oral pellets and oral granules, respectively.
The authors recommend that policy makers work to ensure an adequate supply. Ministries of health need to plan and forecast the potential demand for pellets or granules, as improved manufacturing capacity is anticipated.
While access to pellets and granules is critical in the short- and medium-term, protease inhibitors for children will be replaced with the use of integrase inhibitors.
The current unit cost of pellets is greater than the oral solution. However, supply chain cost advantages, namely lower weight, less storage cost and less wastage offset the higher unit price. When analysing cost, all contributing elements should be considered.
3) Slow uptake by healthcare workers and caregivers
Reluctance to adopt new formulations is common among healthcare workers and caregivers. Oral pellet and oral granule formulation means both groups have to learn a new means of administration, resulting possibly in decreased acceptance and uptake.
The authors recommend that the introduction of new paediatric antiretroviral regimens and formulations should be streamlined. In Kenya and Uganda, information, education and communication materials for policy makers, healthcare workers and caregivers facilitated the introduction of LPV/r oral pellets. The Drugs for Neglected Diseases Initiative is assessing this transition.
Best practices identified and lessons learned can inform the introduction of new paediatric antiretrovirals. Strategies to simplify and standardise administration across regimens and formulations are needed to increase uptake.
Introduction Despite a significant reduction in mother‐to‐child transmission of HIV, an estimated 180,000 children were infected with HIV in 2017, and only 52% of children under 15 years of age living with HIV (CLHIV) are on life‐saving antiretroviral therapy (ART). Without effective treatment, half of CLHIV die before the age of two years and only one in five survives to five years of age.
Discussion Over the past four years, the United States Food and Drug Administration tentatively approved new formulations of lopinavir/ritonavir (LPV/r) in the form of oral pellets and oral granules. However, the slow uptake of the aforementioned formulations in the low‐ and middle‐income countries with the highest paediatric HIV burden is largely due to three challenges: limited manufacturing capacity; current unit cost of the pellets and granules; and slow uptake of these new formulations by policy makers and health care workers.
Conclusions Solutions to overcome these barriers include ensuring availability of an adequate supply of LPV/r oral pellets and oral granules, considering all programmatic and clinical factors when selecting paediatric ART formulations, and leveraging current resources to decrease paediatric HIV morbidity and mortality.
Christine Y Malati, Rachel Golin, Lisa O’Brien, Nandita Sugandhi, Meena Srivastava, Chris Larson, Benjamin R Phelps