Treatment-Emergent Mutations and Resistance in HIV-Infected Children Treated with Fosamprenavir-Containing Antiretroviral Regimens.

Treatment-emergent mutations and drug resistance were analyzed in virus from HIV-infected children meeting virologic failure (VF) criteria over 48 weeks following treatment with unboosted fosamprenavir or fosamprenavir/ritonavir-containing regimens in studies APV20002 and APV29005. Both antiretroviral therapy (ART)-naïve and ART-experienced patients were enrolled. Patients met VF criteria by either failing to suppress HIV-RNA to <400 copies/mL through week 24 or after confirmed viral rebound (≥400 copies/mL) anytime through week 48. Viral isolates were analyzed for treatment-emergent mutations or reduced drug susceptibility. Through week 48, 25/109 (23%) of APV29005 and 9/54 (17%) APV20002 study patients met VF. VF was more common in ART-experienced patients (68% and 78%, respectively). Major or minor treatment-emergent mutations were detected at VF in virus from 3 patients receiving unboosted fosamprenavir-containing regimens and in virus from 10 patients receiving fosamprenavir/ritonavir-containing regimens across the two studies. Major protease inhibitor mutations and the reverse transcriptase mutation M184V were detected at VF in virus from 4 and 5 patients, respectively, across both studies. Reduced drug susceptibility to any drug emerged in virus from 9 patients at VF, although reduced fosamprenavir susceptibility emerged in virus from only 4 patients (2 ART-naïve and 2 ART-experienced). No cross-resistance to the protease inhibitor darunavir was observed. In conclusion, given the high proportion of ART-experienced children (71%) in these two studies, the overall incidence of children meeting VF criteria through 48 weeks was relatively low (21%) and development of fosamprenavir reduced drug susceptibility at VF was uncommon, further supporting the use of fosamprenavir-containing ART regimens in HIV-infected children.

Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations.

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations.