Phenotypic and genotypic inhibitory quotients and virologic response in treatment experienced children
Polly Clayden, HIV i-Base
Natella Rakhmanina from the children’s National Medical Center, Infectious Diseases, Special Immunology and Pharmacology, Washington, showed findings from a study to investigate whether the lopinavir (LPV) phenotypic inhibitory quotient (PIQ) and genotypic inhibitory quotient (GIQ) in treatment experienced children correlate with treatment response, when receiving LPV containing HAART, as observed in treatment experienced adults.
In this study the investigators collected 52 weeks prospective data from children and adolescents aged 4-15 years receiving LPV/r as single PI within antiretroviral regimens. 12-hour pharmacokinetic (PK) samples were collected and LPV susceptibility measured within 3 months of enrollment. Treatment histories, including resistance information, were obtained from medical records. Viral load and self reported adherence were measured 3 monthly.
IQ was calculated as the rate of plasma 12-hour trough concentration (Cmin) after observed dose divided by the protein-adjusted IC50 for PIQ and the number of LPV-associated mutations for GIQ.
In this analysis, 45 PI experienced children and adolescents were followed for 52 weeks. Their median age was 11 (5.3-17.8) years; 24 were girls and the majority (n=41) were African American. Of the group 40 (89%) received background regimens of 2 NRTIs, 2 received 3 NRTIs and 3 received NRTI plus NNRTI.
The median length of PI experience was 5.2 (0.7-9.2) years and of previous LPV exposure was 2.2 (0.5-5.0) years. Self reported adherence was a mean of 88% (41-100%). About half, 24/45(53%), of the patients achieved viral load, 400 copies/mL, at least once during the study. The median LPV Cmin was 6.2 (0.1- 16.7) mg/L.
Median PIQ (n=36) was 12.6 (0.03-231.1). The investigators noted that a baseline PIQ cutoff of 15 (as in adults) did not distinguish those achieving a viral load of <400 copies/mL from those that did not, p=0.09.
In multivariate analysis, only baseline PIQ >25 was significantly associated with viral load <400 copies/mL: 11/16 (69%) patients with PIQ >25 achieved viral load <400 copies/mL vs. 5/20 (20%) with PIQ <25, p=0.01.
The geometric mean PIQ in those patients achieving viral load <400 copies/mL was 16.7 vs 2.4 in those who did not, p=0.09.
The investigators found for every increase in baseline PIQ of 10, the probability of achieving viral load <400 copies/ml, when adjusted for prior duration of LPV treatment, increased 9.6-fold (95% CI 9.2-9.9), p=0.02.
They reported a median GIQ (n=22) of 1.0 (0.03-6.5) and a median of 6 (1-13) LPV mutations per patient. The geometric mean GIQ in those achieving viral load <400 copies/mL was 1.0 vs. 0.7 in those who did not, p=0.56.
The investigators concluded that LPV PIQ was associated with viral load <400 copies in PI experienced HIV-positive children and adolescents but GIQ was not. They suggest that a cutoff of LPV PIQ >25 may be a target for maximising efficacy.
Rakhmanina N et al. The phenotypic and genotypic susceptibility lopinavir scores and virologic response in treatment experienced children with HIV. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract 0_17.