PACTG P1030

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lopinavir is a potent protease inhibitor that is sensitive to pharmacokinetic enhancement by ritonavir (RTV) even at low RTV doses, thus providing therapeutic LPV concentrations over the entire dose interval. As plasma trough concentrations of protease inhibitors have been shown to correlate closely with antiviral effect, this potentially provides a pharmacologic impediment to the emergence of viral resistance (1, 2). Lopinavir/ritonavir has shown significant antiviral activity and tolerability in clinical trials in adults and children >6 months of age (3, 4, 5). In antiretroviral-nanve HIV-infected adults, the combination of LPV 400 mg/RTV 100 mg BID produces a mean LPV trough concentration (Ctrough) which is more than 50 times higher than the EC50 of wild-type HIV (6). In comparison, the Ctrough/EC50 ratio in the presence of human serum for currently available protease inhibitors (PIs) is <4. The pharmacokinetics of LPV 400 mg co-administered with RTV 100 mg BID was studied in 21 HIV-infected adults, without meal restrictions. At study weeks three through four, the mean (+/- SD) pharmacokinetic parameters for LPV included an average 12-hour AUC of 82.8 +/- 44.4 g/ml, a peak plasma concentration of 9.6 +/- 4.4 g/ml, and a trough plasma concentration of 5.5 +/- 4.0 g/ml. The median trough concentration was 4.23 g/ml (Kaletra package insert, Abbott Laboratories, March 2001). It can be argued that once an infant has been vertically infected, the most critical period regarding long-term clinical outcome is the first months of life. Aggressive therapy early in infection may result in a better prognosis. This can be evaluated within the context of viral and cellular dynamics. Luzuriaga et al documented slower viral clearance among the youngest group of infants studied (2 weeks to 3 months of age) compared with older infants (3-24 months of age) with a regimen containing nevirapine but no PI (8). PI-containing regimens studied across the same age groups (PACTG 345) did not reveal age-related differences in viral clearance (9). This remains an open question, and these differences have a potential impact on ultimate clinical course among infants, especially infants under 6 months of age, which is the target population for this study. It is anticipated that a sizeable proportion of participating infants will achieve and maintain non-detectable plasma virus status (<400 or <50 copies/ml). Given that this will be a group of infants identified and aggressively treated very early in infancy (during "primary infection"), there is considerable interest in monitoring residual, viral activity in the form of transcription and competent replication.