2344. FDA Analysis of CD4+ Cell Count Declines Observed in HIV-Infected Children Treated With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide

Elvitegravir (EVG)/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is approved for treatment of HIV-1 in children weighing ≥25 kg based on a Gilead sponsored study of safety, pharmacokinetics (PK), and antiviral activity among 23 virologically suppressed (VS) children 6–<12 years old who switched from a stable antiretroviral (ARV) regimen to E/C/F/TAF. All subjects were perinatally infected with HIV. Though all subjects maintained HIV viral load < 50 copies/mL, a decrease in mean CD4+ cell count (CD4ct) occurred at Week 2 and persisted to Week 24 (Table 1). Mean Change in CD4cta From Baseline (BL) to Week 24 aCells/µL. Mean Change in CD4cta From Baseline (BL) to Week 24 aCells/µL. We explored possible reasons for CD4ct declines including change in overall leukocyte and absolute lymphocyte count (ALC), relationship between CD4ct and PK of each drug in E/C/F/TAF, and trends in subject-level CD4ct. We reviewed prior ARV trials and literature to look for drug class effects. Decreased CD4cts were not explained by declines in total leukocyte counts or ALC. There was no association between CD4ct and area under the curve (AUC) of any of the four drugs. Mean CD4ct decline was not driven by a few outliers; CD4ct declined in 21/23 subjects. Prior ARV trials of VS adults and children, including EVG-containing regimens, show no notable sustained decline in CD4ct. Pediatric studies of other integrase inhibitors (INSTI) in this age group did not have comparable VS subjects. The literature describes structural similarity between human recombinant activation gene (RAG)1/2 and HIV integrase. RAG inhibition by INSTIs could potentially interfere with B and T cell development. EVG exposure in mice at supra-therapeutic concentrations, caused significant reductions in mature B lymphocytes. The relevance of this finding to humans is unclear. Decreased CD4ct is a unique finding in this pediatric study of E/C/F/TAF and the etiology remains unclear. Inhibition of RAG1/2 by EVG may play a role, but further research is needed. No subjects had nadir CD4ct < 350 and no opportunistic infections were reported. However, CD4 declines are included in E/C/F/TAF labeling to alert providers of this potential risk. All authors: No reported disclosures.