Long-term Safety and Efficacy of Atazanavir-based Therapy in HIV-infected Infants, Children and Adolescents

Abstract

Background Atazanavir is an attractive option for the treatment of Pediatric HIV infection, based on once daily dosing and the availability of a formulation appropriate for younger children. PACTG 1020A was a phase I/II open label study of atazanavir (ATV) (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA >5000 copies/ml (cpm) were enrolled at sites in the United States and South Africa. Results Of 195 children enrolled 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose. 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%), had HIV RNA ≤400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤400 cpm; median CD4 increase was 196.5 cells/mm3. The primary adverse event was increased serum bilirubin; 9% of subjects had levels > 5.1 times upper limit of normal and 1.4% noted jaundice. 3% of subjects experienced Grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC >199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary adverse event, as expected, was an increase in bilirubin levels.

Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study

“…Our results are consistent with those of studies in treatment‐naïve HIV‐infected adults, which have shown improved metabolic parameters with newer PIs . Few studies, however, have been published in the paediatric HIV‐infected population on longitudinal lipid changes over time with newer PIs such as ATV/r and DRV/r, and most have been limited by small sample sizes . Similar to our findings, a case series of HIV‐infected children who switched from lopinavir/r to ATV/r or DRV/r reported a significant reduction in TC at 18 months post switch compared with baseline levels, but no changes in TG, HDL‐C or LDL‐C .…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing

“…With once‐daily atazanavir 300 mg plus ritonavir 100 mg, the frequency of grade 3 or higher bilirubin elevations (at least 2.5 times the upper limit of normal) is ∼40%, and of grade 4 (at least 5 times the upper limit of normal) bilirubin elevation is ∼4‐8% . Among children and adolescents in a trial that involved atazanavir, 9% had a bilirubin value ≥5.1 times the upper limit of normal and 1.4% experienced jaundice …”

Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults

“…These mg/m 2 doses are significantly lower than those used in P1020A, where a ATV doses of 520 mg/m 2 in patients aged >2 to 13 years old and 620 mg/m 2 >13 to 21 years old satisfied protocol-defined pharmacokinetic criteria (based on ATV targets achieved in adults receiving ATV/r). Forty-three percent of ARV-experienced children in P1020A achieved a HIV-1 RNA viral load <400 copies/mL at 48 weeks, with no difference between ATV and ATV/r (6). However, it must be noted that in P1020, the pharmacokinetic targets led to equivalent ATV exposure for unboosted and ritonavir boosted doses, which is not the case for adults where ATV exposure is 3- to 4-fold higher with ritonavir boost compared to non-boosted ATV (7) [and was reported to result in better virologic outcomes (8).…”

“…Our data support the need for a much higher dose than is currently recommended as both the ATV 400 and 600 mg dose in our study produced exposures in adolescents and young adults below those achieved with ATV/r that achieve a good virologic response in adults (9). The impact of higher unboosted doses on the virologic efficacy in this heavily treated group is difficult to extrapolate but the safety data reported with higher ATV exposure in these children and adolescents are reassuring (6). However, the fact that more than a third of our subjects had a C 24 below 0.15 mg/L, (the proposed trough concentration cut-off for virologic efficacy) and the substantial individual variability are of concern despite the fact that unboosted ATV has been licensed at a once-daily dose for treatment-naïve patients.…”