4Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. ACE inhibitors are associated with adverse side effects such as persistent dry cough (ACE-cough) and, rarely, life-threatening angioedema (ACE-AE). The authors investigated the influence of ACE I/D polymorphism in combination with serum ACE activity, B 2 receptor À9/+9 polymorphism, and B 2 receptor C-58T single nucleotide polymorphism (SNP) on the development of ACE-AE and ACE-cough. The frequencies of ACE I/D as well as B 2 receptor +9/À9 and C-58T polymorphisms were compared in patients with ACE-AE, ACE-cough, and ACE inhibitor-exposed controls, and serum ACE activity was measured. There were 52 cases of ACE-AE, 36 cases of ACE-cough, and 77 controls. The genotyping revealed a significant association between the B 2 À9 allele and ACE inhibitor-induced AE (62% vs 38%, P=.008), and ACE inhibitor-induced cough (61% vs 38%, P=.02) when compared with controls. There was no significant association between ACE I/D polymorphism as well as the B 2 C-58T
Background Poor adherence to antiretroviral therapy contributes to pharmacokinetic variability and is the major determinant of virological failure. However, measuring treatment adherence is difficult, especially in children. We investigated the relationship between plasma lopinavir concentrations, pretreatment characteristics and viral load >400 copies/ml. Methods A total of 237 HIV-infected children aged 4–42 months on lopinavir/ritonavir oral solution were studied prospectively and followed for up to 52 weeks. Viral load and lopinavir concentration were measured at clinic visits 12, 24, 36 and 52 weeks after starting treatment. Cox multiple failure events models were used to estimate the crude and adjusted effect of lopinavir concentrations on the hazard of viral load >400 copies/ml. Results The median (IQR) pretreatment CD4+ T-lymphocyte percentage was 18.80% (12.70–25.35) and 53% of children had a pretreatment viral load >750,000 copies/ml. The median (IQR) weight-for-age and height-for-age z-scores were −2.17 (−3.35–−2.84) and −3.34 (−4.57–−3.41), respectively. Median (IQR) lopinavir concentrations were 8.00 mg/l (4.11–12.42) at median (IQR) 3.50 h (2.67–4.25) after the dose. The hazard of viral load >400 copies/ml was increased with lopinavir concentrations <1 mg/l versus ≥1 mg/l (adjusted hazard ratio 2.3 [95% CI 1.63, 3.26]) and lower height-for-age z-scores. Conclusions Low lopinavir concentrations (<1 mg/l) are associated with viraemia in children. This measure could be used as a proxy for adherence and to determine which children are more likely to fail.
Background Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long term viral suppression have not been adequately defined in children. Aim We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy. Methods After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to remain on a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post-randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL) Results At randomization, the median (IQR) age, CD4+ T-Lymphocyte percentage, weight-for-age and weight-for-height z-scores were 19 (16–24) months, 29 (23–37) %, −0.6(−1.3 to 0.2) and −3.2 (−4.1 to −2.1) respectively. The proportion of children with viral load 51–400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1mg/L vs ≥1mg/L (adjusted hazard ratio 0.62 [95% CI, 0.40–0.94]) and for children with viral loads 51–400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia. Conclusion Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1mg/L of lopinavir to ensure sustained viral suppression.
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