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test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

During HIV infection, the immune system plays a role in controlling viral replication by eliciting antibodies that work in collaboration with effector cells such as natural killer (NK) cells. These mechanisms are mediated by Fc receptors for immunoglobulins (Ig). Depending on receptor type, Fc Gamma Receptors (FCGR) can regulate immunity by causing cell activation or inhibition in response to infections. Among different patients, there are differences in progression and treatment outcome. One of the factors hypothesized to be the cause of these differences is FCGR polymorphisms. Furthermore, genetic variations that occur in FCGR genes such as Copy Number Variations (CNV) and Single Nucleotide Polymorphisms (SNPs) have been shown to affect Fc-mediated effector functions. These genetic variations could modify FcR expression and IgG isotype binding, which would affect HIV infection risk and disease progression.

Although the burden of HIV infection in Africa is high, data is lacking on the effect of FCGR polymorphisms on the progression of the infection and the response to antiretroviral therapy (ART) in African populations. Therefore, the project aims to determine this effect in a Ghanaian population. The study will genotype FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa and FcγRIIIb small nucleotide polymorphisms (SNPs), copy number variations (CNV), and determine their allelic and haplotype associations with HIV infection progression and ART outcomes.

HIV patients will be recruited and followed up every three months over two years. Baseline viral loads will be determined before ART and pretreatment viral load, CD4 count and FCGR types (using amplicon targeted deep sequencing techniques) will be compared to determine who responds at what rate (through measurement of drug levels and ART resistance levels) and how that relates to their FC gamma haplotypes.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

The knowledge generated may help explain why certain ARTs work better for some patients but not others. This would also show the need to consider FCGR genotypes before prescribing specific drugs for HIV patients.

As a capacity development project, Dr Lamptey will have the opportunity to use the advanced skills in sequencing acquired during the fellowship, develop her competence in HIV immunology, and support her becoming an independent investigator in HIV translational research at the Noguchi Memorial Institute for Medical Research in Ghana. She will also transfer knowledge and skills to students and colleagues through training and mentorship.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact