Protease inhibitor (PI) monitoring may improve the care of human immunodeficiency virus (HIV)-infected patients; however, pediatric data are limited. A high-performance liquid chromatographic (HPLC) assay developed for the simultaneous determination of indinavir, ritonavir, saquinavir, and nelfinavir in 0.2 mL of plasma was used to quantify PI concentrations in HIV patients. The reliability, sensitivity, and specificity of the assay were first verified in stored adult samples. Later, blood collected prospectively from patients aged 2.9 to 42 years of age (10 adults aged 24 to 42 and 15 children aged 2.9 to 18 years) was tested. Nondetectable (below 25-50 ng/mL) concentrations (ND) were found in 33% of adult samples and 24% of pediatric samples. Four patients taking from 13.7 to 28 mg/kg/d of ritonavir (mean of 21.3) had concentrations ranging from ND to 11.4 microg/mL, quite different from predicted values. Correctable, important clinical problems including drug-drug interactions, drug administration problems, and confirmed noncompliance were identified and corrected using modern therapeutic drug monitoring (TDM) techniques. Routine PI monitoring and interpretation (TDM) could improve the care of adult and pediatric HIV patients; especially in patients who do not respond as expected to treatment, develop viral resistance or toxicity, and have questionable compliance.
BackgroundMany children born to HCV-infected mothers in the U.S. never receive recommended anti-HCV antibody (Ab) screening at age ≥ 18 months. Earlier testing by HCV-RNA PCR might facilitate increased screening, though prior studies using older PCR assays reported unacceptably low sensitivity of one-time PCR testing in infants. We hypothesized that testing at age 2–6 months using modern blood HCV-RNA PCR platforms with enhanced analytical sensitivity and reliability will adequately detect infected infants.MethodsMedical records of vertically exposed infants tested for HCV-RNA at age 2–6 months at Nationwide Children’s Hospital from January 1, 2008 to December 31, 2017 were reviewed. HCV-RNA tests included qualitative (in-house) and quantitative (ARUP reference lab) Cobas Taqman RT-PCR assays (Roche) with lower limits of detection of 1.2–1.9 log10 IU/mL. Diagnostic performance of early PCR screening was determined using a composite gold standard: (1) infected children had ≥ 2 positive PCRs or persistently positive Ab after age 24 months; (2) uninfected children lacked these criteria and required documentation of a negative Ab at a point after age 18 months.ResultsDuring the study period, 639 vertically exposed infants underwent HCV-RNA testing at age 2–6 months. Of these, 24 (3.8%) tested positive, consistent with prior estimates of the vertical transmission rate. Blood HCV-RNA levels were high at screening (median 6.7 log10 IU/mL, range 5.2–7.8 log10 IU/mL), and confirmatory PCR tests were positive in all who had repeat testing (n = 22). Among 615 infants with negative PCR screening, 444 had reached age ≥ 18 months, of whom 144 had undergone Ab testing. Ab tests were negative in 142, while two children had low positive Ab results at 18 months. In both cases, repeat PCR and repeat Ab after age 24 months were negative, suggesting waning maternal Ab rather than true infection. Using the composite gold standard there were 22 true positive, 0 false-positive, 144 true negative, and 0 false negative cases, yielding a sensitivity of 100% (95% CI: 85–100% [Wilson-Brown]).ConclusionThese findings demonstrate that modern blood HCV-RNA PCR assays have excellent sensitivity for detecting vertically infected infants as early as 2–6 months of age and may improve HCV surveillance given the substantial number of children lost to follow-up prior to 18 months Ab screening. Disclosures All authors: No reported disclosures.
PROTEASE INHIBITOR TDM: This study examines the importance of therapeutic drug monitoring (TDM) of protease inhibitors (PI) in adults and children infected with the human immunodeficiency virus (HIV). Pediatric patients were included because information in this population is limited. A high performance liquid chromatographic (HPLC) assay measured indinavir, saquinavir, ritonavir and nelfinavir simultaneously in 0.2 mL of plasma. Initially, the reliability, sensitivity and specificity of the assay were verified in stored samples of plasma from adult patients who had been receiving PIs. Non-detectable concentrations (ND) were <25-50 ng/mL. In 96 out of 293 stored samples from adult patients, selected randomly, concentrations of PIs were ND. In a second prospective study of 10 adults (9 mothers and one father, aged 24-42 years) and 15 children (2.9-18 years) ND levels of PI were observed frequently (27% or 4 out of 15 pediatric subjects). In the latter study, drug-drug interactions, dosing errors, noncompliance and other important problems were identified and corrected. Routine monitoring and interpretation of PI concentrations (TDM) may improve the management of adult and pediatric patients infected with HIV, especially in those who fail to respond, develop adverse effects or viral resistance, or lack compliance.
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