Safety Of Atazanavir/Ritonavir With Tenofovir Disoproxil Fumarate In Hiv-Infected Adolescents

Background: Atazanavir/ritonavir(ATV/r) and tenofovir disoproxil fumarate(TDF) are recommended once-daily antiretroviral therapy, particularly for second-line therapy. Their concomitant use can lead to decrease in ATV and increase in TDF plasma concentration. There are limited data of efficacy and safety of their co-administration in children and adolescents. Methods & Materials: Nineteen HIV-infected Thai children aged 6-18years, body weight 25-50 kg, and total bilirubin<2 mg/dL were enrolled. They were either PI-experienced with HIV-RNA<50copies/ml or PI-naïve with HIV-RNA≥1,000copies/ml. ATV(Reyataz®) 200 mg/capsule with generic ritonavir 100 mg/tablet, produced by the Thai Government Pharmaceutical Organization, were co-administered with TDF and lamivudine once daily. CD4, HIV-RNA, total bilirubin, creatinine, lipids, lumbar spine bone mineral density(BMD) were performed at baseline and week 48. Results: Fifty-eight% were female. The median(IQR) age was 13.6(11.9–14.7) years, body weight was 34.9(30.5–39.7) kg and CD4 was 670(540–1233)cells/mm3. At screening, 17 children used lopinavir/ritonavir-based regimen with lamivudine(82%), zidovudine(47%), didanosine(41%), and TDF(18%) and 2 were PI-naïve. At week 48, median CD4 was 710(557-1051) cells/mm3 (p=0.8). HIV-RNA<50copies/ml were observed in 84% of children[15/17 of PI-experienced and 1/2 of PI-naive children]. No serious adverse event was reported. Mean total bilirubin rose from 0.7 mg/dL at baseline to 1.5 mg/dL at week 48 (p<0.001), with 32% of children having levels >2 mg/dL (p=0.03). Proportion of children with creatinine clearance by Schwartz formula < 90 mL/min/1.73m2 rose from 11% at baseline to 67% t week 48 (p<0.01). However, none had creatinine clearance <60 mL/min/1.73m2. Proportion with triglyceride>130 mg/dL declined from 53% to 21% (p=0.03). The other lipid markers were unchanged. Lumbar spine BMD Z-score at baseline was -1.40 (0.93) and at week 48 was 0.72 (0.10) (p=0.1). Proportion with lumbar spine BMD Z-score< -1.5 at baseline vs. week 48 was 56% vs. 68% (p=0.50). Proportion with lumbar spine BMD Z-score< -2.0 at baseline vs. week 48 was 25% vs. 44% (p=0.25). Conclusion: Second-line atazanavir/ritonavir 200/100 mg with TDF and lamivudine was effective. However, the clinical impact of the total bilirubin rise and the creatinine clearance decline requires long-term monitoring.