Secondary Logo

Share this article on:

Safety and Efficacy of Atazanavir Powder and Ritonavir in HIV-1-Infected Infants and Children From 3 Months to <11 Years of Age: The PRINCE-2 Study

Cotton, Mark, F., MMed, PhD*; Liberty, Afaaf, MBChB; Torres-Escobar, Indiana, MD, MSc, PhD; Gonzalez-Tome, Maria, Isabel, PhD§; Lissens, Jurgen, MSc; Zaru, Luna, PhD; Klauck, Isabelle, MD**; Cambilargiu, Daniela, MD††; Pikora, Cheryl, MD, PhD‡‡; Correll, Todd, A., PharmD§§

The Pediatric Infectious Disease Journal: June 2018 - Volume 37 - Issue 6 - p e149–e156
doi: 10.1097/INF.0000000000001856
HIV Reports

Background: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children.

Methods: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV + RTV) plus optimized dual nucleos(t)ide reverse transcriptase inhibitors therapy in antiretroviral-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children 3 months to <11 years received ATV + RTV by 5 baseline weight bands: 5 to <10 kg = 150/80 mg; 5 to <10 kg = 200/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg; and 25 to <35 kg = 300/100 mg.

Results: Of 99 treated children, 83.8% and 59.6% remained on ATV powder until 24 and 48 weeks, respectively. Through 48 weeks, the most common adverse events were upper respiratory tract infections (33.3%), gastroenteritis (28.3%), vomiting (21.2%) and hyperbilirubinemia (18.2%; none leading to treatment discontinuation). Serious adverse events occurred in 20.2% of patients. Laboratory grade 3–4 hyperbilirubinemia occurred in 9.2% and elevated total/pancreatic amylase in 33.7%/3.1%. At week 24, proportions with virologic suppression (HIV-1 RNA <50 copies/mL; intention-to-treat analysis) across weight bands were 10/23 (43.5%), 2/12 (16.5%), 10/21 (47.6%), 19/35 (54.3%) and 5/8 (62.5%), respectively. Virologic suppression was similar in antiretroviral-naïve/experienced patients and lowest in the 5 to <10 kg = 200/80 mg group, likely because of higher baseline HIV-1 RNA and discontinuation (66.7%). Overall, virologic suppression at weeks 24 (46.5%) and 48 (43.0%) was comparable. At week 48, 83.3% and 74.1% of caregivers reported no trouble giving ATV powder and RTV, respectively.

Conclusions: ATV powder palatability, efficacy and lack of unexpected safety findings support its use for HIV-1-infected children ≥3 months to <11 years.

From the *Children’s Infectious Diseases Clinical Research Unit, Department of Pediatrics & Child Health, Stellenbosch University, Tygerberg, South Africa

Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa

Faculty of Medicine, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico

§Pediatric Infectious Diseases Department, Hospital 12 de Octubre, Madrid, Spain

Bristol-Myers Squibb, Braine L’Alleud, Belgium

Bristol-Myers Squibb, Hopewell, New Jersey

**Bristol-Myers Squibb, Rueil-Malmaison, France

††Bristol-Myers Squibb, Buenos Aires, Argentina

‡‡Bristol-Myers Squibb, Wallingford, Connecticut

§§Bristol-Myers Squibb, Princeton, New Jersey.

Accepted for publication October 25, 2017.

This study was supported by Bristol-Myers Squibb, the manufacturer of atazanavir. M.F.C. declares funding for his institution from Bristol-Myers Squibb for the conduct of the present study; his institution has received other funding for pharmaceutical trials from ViiV Healthcare, Gilead Sciences, Novovax, VPM-Gmbh, and Novartis and NIH funding: NIAID through IMPAACT and ACTG trial networks and NIMH. I.T.-E. declares receiving honoraria for speaker engagements for Merck Sharpe & Dohme; Stendhal Pharma, and AbbVie. M.I.G.-T. declares receiving honoraria for speaker engagements for ViiV Healthcare, Janssen-Cilag and AbbVie; she has also received a Gilead fellowship. J.L., L.Z., I.K., D.C., and T.A.C. are all employees of and own stock in Bristol-Myers Squibb. C.P. was an employee of Bristol-Myers Squibb at the time this study was conducted and is now an employee of Gilead Sciences, Inc. A.L. has no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com)

Address for Correspondence: Mark F. Cotton, MMed, PhD, Faculty of Medicine Health Sciences, Stellenbosch University, Ward J8, Tygerberg Academic Hospital, Francie Van Zijl Drive, Parow Valley, PO Box 241, Cape Town 8000, South Africa. E-mail: mcot@sun.ac.za.

Current international treatment guidelines recommend initiating antiretroviral (ARV) therapy for all HIV-infected children, regardless of clinical, virologic or CD4 criteria.1 , 2 Preferred first-line regimens if <3 years include 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with ritonavir-boosted lopinavir (LPV + RTV)1 , 2 or raltegravir,2 and for those between 3 and 10 years, abacavir + lamivudine + efavirenz1 or 2 NRTIs with ritonavir-boosted atazanavir (ATV + RTV), ritonavir-boosted darunavir, efavirenz, LPV+RTV or raltegravir.2

Fewer clinical trials evaluating efficacy, safety, pharmacokinetics (PK), and optimal dosage of ARV formulations have been conducted in young children than in adults.

Atazanavir (ATV), a HIV-1 protease inhibitor (PI) given once daily, is indicated for adults and children. ATV is available in capsule (150, 200 and 300 mg) formulations globally.3–5 More recently, an oral powder formulation (50 mg ATV per gram of powder) was developed for infants and young children,3 where LPV + RTV may be poorly tolerated. Other PIs currently available as liquid formulations/reconstituted oral suspensions for children include darunavir (for children 3 to ≤18 years of age; oral suspension approved in the United States and European Union [EU]),6 fosamprenavir (for children 2–18 years; oral suspension approved in the United States),7 co-formulated LPV + RTV (for infants and children ≥14 days; licensed worldwide via the Medicines Patent Pool)8 , 9 and LPV+RTV 40/10 mg oral pellets (tentative approval restricted to the President’s Emergency Plan for AIDS Relief in resource-limited countries).10

ATV powder plus RTV has been evaluated in 3 separate pediatric studies: IMPAACT 1020A (AI424-020/NCT00006604),11 , 12 PRINCE-1 (AI424-397/NCT01099579)atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13 and PRINCE-2 (AI424-451/NCT01335698). The PRINCE studies used weight-based ATV powder doses from model-based simulations (including covariates such as body weight, clearance, and relative bioavailability of different formulations) predicted to produce ATV exposures similar to those in adults receiving the recommended ATV + RTV dose of 300/100 mg capsules (Bristol-Myers Squibb data on file), based on predefined exposure similarity criteria described previously.14 ATV powder is currently approved in the United States and European Union for those ≥3 months and weighing ≥5 kg.4 , 15 Regulatory submissions for ATV powder are currently underway globally.

Here, we present safety, efficacy and acceptability of ATV + RTV over 48 weeks in ARV-naive and -experienced pediatric patients 3 months to <11 years at enrollment (PRINCE-2 study). A PK and pharmacodynamic analysis using data from PRINCE-1 and PRINCE-2 studies is presented in an accompanying article. Results from PRINCE-1 are reported elsewhere.atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13

Back to Top | Article Outline

MATERIALS AND METHODS

Design

This ongoing phase 3b, prospective, international, multicenter, nonrandomized, single-arm, 2-stage study is conducted at 24 centers in Argentina, Brazil, Chile, Mexico, Poland, Romania, Russia, South Africa, Spain and the United States. HIV-1-infected participants ≥3 months to <11 years and weighing ≥5 kg and <35 kg were enrolled. PRINCE-2 commenced in November 2011; Stage 1 was completed in September 2014, comprising a maximum of 48 weeks on ATV powder, and reported here. Stage 2 data collection, for long-term safety of ATV powder up to 18 years of age, is ongoing.

The study was conducted according to Good Clinical Practice, as per the International Conference on Harmonisation, and the ethical principles underlying EU Directive 2001/20/EC and US Code of Federal Regulations, Title 21, Part 50 (21CFR50). The study was approved by institutional review boards and independent ethics committees for participating centers. Informed consent was obtained from all parents/legal guardians and from minors able to assent. An independent data monitoring committee oversaw study progress.

Back to Top | Article Outline

Patients

Inclusion criteria were as follows: ARV-naive or -experienced patients with a screening plasma HIV-1 RNA level ≥1000 copies/mL. Treatment experience was defined as having previous exposure to ARVs, either as prior treatment for HIV-1 or as post-exposure prophylaxis with ≥1 ARV to prevent vertical transmission. ARV-naïve patients had to show genotypic sensitivity to ATV at screening and to both components of a locally approved NRTI backbone. ARV-experienced patients had to show both genotypic and phenotypic sensitivity to ATV and the 2 NRTIs at screening.

Exclusion criteria included previous exposure to ATV or prior history of ≥2 failures during PI treatment; documented cardiac conduction abnormality or significant cardiac dysfunction or a history of syncope; or either hepatitis B or C virus co-infection.

Back to Top | Article Outline

Treatments

Children 3 months to <11 years of age were dosed with ATV powder and RTV liquid, capsules or tablets according to baseline weight bands. Four weight-band ATV + RTV dosing groups were planned: 5 to <10 kg = 150/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg and 25 to <35 kg = 300/100 mg. After an interim PK analysis in PRINCE-1, an additional group (5 to <10 kg = 200/80 mg) was added to determine if ATV exposure could be enhanced by an increased dose in this weight band. The site investigator selected the 2 NRTIs based on availability, viral resistance and treatment history. Tenofovir disoproxil fumarate, which decreases ATV through concentration by 23%, was excluded.3

Stage 1 comprised a maximum of 48 weeks on ATV powder. Children reaching 35 kg before 48 weeks required transitioning onto ATV capsules and entered stage 2. Children not reaching 35 kg during stage 1 continued ATV powder during stage 2. It was originally planned to assess ATV powder safety and efficacy when all children had completed the 48-week stage 1 period; however, the study protocol was amended to conduct the primary outcome evaluation at week 24 instead of week 48, based upon guidelines from EU regulatory authorities.16 Consequently, 13 children did not reach week 48 when the last treated child had reached week 24. In this report, the analysis of safety and acceptability/palatability through a maximum of 48 weeks was based upon data collected during this amended definition of stage 1. An additional efficacy analysis was later performed using updated data for all children reaching week 48.

Back to Top | Article Outline

Outcomes

Primary Outcome

The primary outcome was the safety of RTV-boosted ATV powder through a maximum of 48 weeks. Safety outcomes included the frequency of adverse events (AEs), serious AEs (as judged by the investigator), AEs leading to discontinuation, Centers for Disease Control and Prevention Class C AIDS events, other significant AEs and laboratory abnormalities.

Back to Top | Article Outline

Secondary Outcomes

The efficacy of ATV powder was measured by the proportion of patients with HIV-1 RNA <50 or <400 copies/mL at week 24 (primary efficacy analysis) and at week 48 using the Roche Amplicor HIV-RNA Assay (version 1.5; Roche Diagnostic Systems, Inc., Branchburg, NJ) or the Abbott RealTime HIV-1 assay (Abbott Molecular Inc., Des Plaines, IL) after the Roche assay was discontinued in August 2014. Efficacy outcomes were summarized by the 5 ATV + RTV dosing categories and by prior ARV experience. Other efficacy assessments included CD4+ cell counts and percentages. For resistance testing methods, see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C888.

Back to Top | Article Outline

Exploratory Outcomes

Acceptability and palatability of ATV powder and RTV through a maximum of 48 weeks were assessed through a caregiver questionnaire at each study visit. Caregivers were asked if their child had trouble completing the dose of ATV powder or RTV (acceptability). Reasons for having trouble completing the dose included general dislike of taking medicines, specific dislike of the study medication’s taste (palatability) and regurgitation of the dose.

PK results of ATV powder administered with RTV were evaluated with the recently completed PRINCE-1 study and are presented in an accompanying publication.

Back to Top | Article Outline

Statistical Analyses

No statistical comparisons were conducted. The week 24/week 48 ATV powder cohort was defined as treated patients not switching to ATV capsules before or within the week 24/week 48 efficacy analysis window (week 18 to <week 30/week 42 to <week 54) or before their HIV-1 RNA week 24/week 48 assessment. Response rates through week 24 (or week 48) for the ATV powder cohort used a snapshot algorithm employing the last HIV-1 RNA in the predefined efficacy window to determine response. In a modified intent-to-treat analysis, the numerator was based on patients meeting the response criteria (ie, on-treatment HIV-1 RNA <50 or <400 copies/mL at the analysis week, with discontinuation considered as virologic failure). The denominator was all patients in the cohort. Observed value analysis was also reported, where the denominator was patients with available HIV-1 RNA values at the analysis week. For the percentages of patients with virologic suppression, exact binomial 95% confidence intervals were calculated. All analyses were conducted using the statistical software SAS version 9 (SAS Institute, Inc., Cary, NC).

Back to Top | Article Outline

RESULTS

Patients

Of 160 screened patients from 24 centers, 99 (62%) were enrolled and treated, of whom 83 (83.8%) and 59 (59.6%) remained on ATV powder for up to 24 and 48 weeks, respectively (Table 1). Over 48 weeks, the most common reasons for discontinuing ATV powder were lack of efficacy (11 patients, 2 of whom had resistance to the assigned NRTI lamivudine at baseline), AEs, and withdrawal of consent (Table 1). Eight children transitioned to capsules and entered stage 2. Excluding these patients, the proportion discontinuing was highest in the 5 to <10 kg = 200/80 mg group in the first 24 weeks (5/12; 41.7%). The reasons for discontinuations included AEs (pulmonary tuberculosis and abnormal amylase; both considered unrelated to study therapy by the investigator), withdrawal of consent owing to geographical relocation, lost to follow-up and no longer meeting study criteria (patient discontinued study therapy at week 4 after confirming elevated transaminases before starting ATV + RTV).

TABLE 1

TABLE 1

Overall, 51 patients (51.5%) were female, 64 patients (64.6%) were from Africa and 62 patients (62.6%) were ARV experienced. Baseline viral load and the proportion of ARV-experienced patients were highest in the 5 to <10 kg = 200/80 mg group (Table 2).

TABLE 2

TABLE 2

Back to Top | Article Outline

Safety

General Adverse Events

No deaths or unexpected safety events were reported. Through week 48, most patients receiving ATV powder (85.9%) had AEs; the most common being upper respiratory tract infections, gastroenteritis and vomiting (Table 3). Hyperbilirubinemia occurred in 18.2% (none led to discontinuation) and rash in 11.1% (3.0% considered related to study therapy). One child in the 15 to <25 kg = 250/80 mg group had treatment-related first-degree atrioventricular block not requiring specific intervention or ATV + RTV interruption.

TABLE 3

TABLE 3

Serious AEs occurred in 20.2% of patients; serious AEs reported in at least 2 patients in any group were alanine aminotransferase increase in 3.0%, overdose in 2.0% and hyperbilirubinemia related in 2.0% (“hyperbilirubinemia” and “blood bilirubin increased”). For a detailed summary, see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C888.

Back to Top | Article Outline

Adverse Events Leading to Discontinuation

AEs led to discontinuation in 7 children. AEs considered related to study therapy by the investigator included acute pancreatitis with increased amylase and lipase in the 5 to <10 kg = 150/80 mg group (n = 1); vomiting in the 10 to <15 kg = 200/80 mg group (n = 1) and in the 25 to <35 kg = 300/100 mg group (n = 1; also reported a bad taste with increased pancreatic amylase). AEs considered unrelated to study therapy by the investigator included abnormal pancreatic amylase without pancreatitis in the 5 to <10 kg = 200/80 mg group (n = 1); raised alanine/aspartate aminotransferases in the 10 to <15 kg = 200/80 mg group (n = 1); pulmonary tuberculosis in the 5 to <10 kg = 200/80 mg group (n = 1) and lymph node tuberculosis in the 15 to <25 kg = 250/80 mg group (n = 1). Both tuberculosis cases required co-treatment with rifampicin, which reduces ATV exposure through CYP3A4 induction.17

Back to Top | Article Outline

Laboratory Abnormalities Through Week 48

Overall, the most common grade 3–4 laboratory abnormality was elevated amylase (Table 3) in 33/98 patients (33.7%), in whom 30 (90.9%) had normal pancreatic amylase. Grade 3–4 total bilirubin elevations occurred in 9/98 patients (9.2%) and elevations of any grade in 44/98 (44.9%).

Back to Top | Article Outline

Efficacy

Virologic and Immunologic Efficacy

Two patients in the highest baseline weight group had transitioned to capsules by the primary week 24 efficacy analysis. Using a modified intent-to-treat approach based on the week 24 ATV powder cohort (ie, patients who did not switch to ATV capsules before or within the week 24 window), 46/99 patients (46.5%) had HIV-1 RNA levels <50 copies/mL and 65/99 (65.7%) had HIV-1 RNA levels <400 copies/mL. At week 24, the proportion achieving virologic suppression trended higher as baseline weight increased but was lowest in the 5 to <10 kg baseline weight band receiving ATV + RTV 200/80 mg (Figs. 1 and 2: overall bars).

FIGURE 1

FIGURE 1

At week 24, median changes from baseline in HIV-1 RNA were −2.17, −3.68, −3.17, −2.80 and −2.08 log10 copies/mL in the 5 ATV + RTV groups, respectively. Corresponding median changes from baseline in CD4 cell count (percent) were 104 (5.0%), 34 (4.5%), 257 (8.5%), 297 (6.0%) and 70 (0.5%), respectively.

Interpretation of virologic suppression by baseline weight bands for the week 48 ATV powder cohort was complicated as 6 patients (3 in the 15 to <25 kg baseline weight band and 3 in the 25 to <35 kg baseline weight band) had transitioned to ATV capsules by the week 48 efficacy analysis (Fig. 1). However, the overall proportions of patients achieving virologic suppression to HIV-1 RNA levels of <50 and <400 copies/mL at week 48 (43.0% and 60.2%, respectively) were similar to those at week 24 (46.5% and 65.7%, respectively; Fig. 2).

FIGURE 2

FIGURE 2

The proportions achieving virologic suppression were similar between the ARV-naïve/experienced patients at either week 24 or at week 48 (Fig. 2). At week 24, the median changes from baseline in HIV RNA were −3.10 and −2.56 log10 copies/mL in ARV-naive/experienced patients, respectively.

Back to Top | Article Outline

Resistance Data

By week 48, 36 patients met criteria for resistance testing: 11 (30.6%) were previously ARV naïve and 25 (69.4%) were ARV experienced. Baseline genotypic and phenotypic results were available for 35 and 26 patients, respectively. One treatment-experienced patient in the 10 to <15 kg = 200/80 mg group developed an emergent minor PI resistance mutation by 24 weeks (V82VAIT; IAS-USA 2013 classification) without phenotypic resistance to ATV and thereafter a major PI resistance mutation (I84V), also without phenotypic resistance to ATV. Three patients developed M184V mutation (one of whom also had I84V described above). All 3 exhibited phenotypic resistance to emtricitabine and lamivudine plus decreased susceptibility to didanosine. Two subjects with pretreatment M184V mutations and phenotypic resistance to emtricitabine and lamivudine developed decreased susceptibility to didanosine.

Back to Top | Article Outline

Acceptability/Palatability

At week 24, most caregivers mixed ATV powder with water (48.2%) or milk (27.7%). Corresponding values over 48 weeks were 53.7% and 22.2%, respectively. At week 24, 86.7% and 80.7% of caregivers reported no trouble giving ATV powder and RTV, respectively. Corresponding values over 48 weeks were 83.3% and 74.1%, respectively. At week 24, 10.8% and 15.7% of caregivers reported that their children disliked the taste of ATV powder and RTV, respectively. Corresponding values over 48 weeks were 13.0% and 22.2%, respectively.

Back to Top | Article Outline

DISCUSSION

In the current study, RTV-boosted ATV powder plus optimized dual NRTI background therapy in infants and children 3 months to 11 years was generally safe and well tolerated. The safety profile of ATV powder was similar to that for capsules in adults18–20 and in infants and children.12 , atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13

Hyperbilirubinemia is an expected consequence of ATV inhibition of uridine 5′-diphospho-glucuronosyltransferase.21 The frequency of grade 3–4 hyperbilirubinemia in the current study (9.2%) was comparable to that in the PRINCE-1 study (9.4%)atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13 but lower than in adults (44%–58%).18 , 19 , 22–24 Although grade 3–4 elevations in serum amylase occurred in 33 patients, pancreatic amylase fraction was elevated in only 3 of 33; only 1 patient developed acute pancreatitis. Prolongation of the PR or QTc interval is observed with ATV in adults3 and in children ≥6 years of age.12 In the current study, which excluded patients with documented cardiac abnormalities at baseline, one child experienced self-limited first-degree atrioventricular block considered related to ATV therapy, requiring no specific treatment, nor discontinuation of ATV powder.

Virologic efficacy of ATV powder at week 24 (the primary efficacy analysis) trended higher across increasing baseline weight bands, with 46.5% and 62.5% of children achieving HIV-1 RNA <50 copies/mL overall and in the highest baseline weight band, respectively. Similarly in PRINCE-1, the overall proportion with HIV-1 RNA <50 copies/mL at week 24 was 46.3%.atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13 The assessment of the durability of virologic efficacy at week 48 by baseline weight bands was complicated by 8 patients in the highest baseline weight bands transitioning to ATV capsules during weeks 24–48 and, therefore, excluded from this analysis. However, the overall proportion of children achieving virologic suppression at week 24 was maintained at week 48 (Fig. 2). For the 12 infants in the 5 to <10 kg = 200/80 mg group, virologic efficacy at weeks 24 and 48 was below that for the 23 infants in the same baseline weight band receiving ATV + RTV 150/80 mg. PK reasons were an unlikely explanation for this difference as ATV exposures were higher in the 5 to <10 kg = 200/80 mg group than in the 5 to <10 kg = 150/80 mg group (steady state ATV minimum concentrations 24 hours post dose were 550 versus 336 ng/mL, respectively, during an intensive PK analysis, see accompanying publication). Rather, the most likely explanation was the higher baseline viral load in these 12 infants and the higher rate of discontinuation during the first 24 weeks of therapy (5/12; 41.7%), occurring for diverse reasons that appeared unrelated to study therapy. However, the lower proportion achieving virologic suppression in the 5 to <10 kg = 150/80 mg group compared with the higher baseline weight bands might be explained by PK reasons (ATV minimum concentrations 24 hours post dose were 336 versus 468–686 mg/dL, see accompanying publication). Further follow-up data on RTV-boosted ATV powder in infants weighing <10 kg may be useful to confirm efficacy and safety in infants. Neither prior ARV experience nor treatment-emergent resistance contributed to differences in proportions of patients achieving virologic suppression.

Owing to the design of PRINCE-2 where 2 and 6 patients in the highest weight bands transitioned to capsules before the week 24 and week 48 efficacy analyses, respectively, it was not possible to directly compare efficacy between this study and PRINCE-1 or other pediatric studies evaluating PI-containing regimens. However, in PRINCE-1, efficacy of RTV-boosted ATV powder combined with optimized dual NRTI therapy was comparable with pediatric studies evaluating RTV-boosted lopinavir or alternative PI-based regimens.atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13

The majority of caregivers in this study considered that their children had no difficulty taking ATV powder (83.3%) or RTV liquid (74.1%), and a low proportion of caregivers reported that their children disliked the taste of ATV powder (13.0%). A higher proportion of caregivers reported that their children disliked the taste of RTV liquid (22.2%). These palatability findings were similar to those in PRINCE-1atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">13 and compared favorably to a minitab sprinkle formulation of RTV-boosted lopinavir in children <4 years whose caregivers reported that 38%–53% disliked the taste of the sprinkles.25

This study has limitations. Only small numbers of HIV-1-infected children were enrolled in each ATV + RTV dosing category (particularly the 5 to <10 kg = 200/80 mg and 25 to <35 kg = 300/100 mg groups). Further data on using RTV-boosted ATV powder, especially in infants weighing <10 kg, is required (see accompanying publication). This study was nonrandomized with no statistical comparisons between baseline weight bands or by prior ATV experience. At week 48, 22.2% of children were reported by their caregivers to dislike the taste of RTV liquid. This contrasts with a recent retrospective review of 119 HIV-infected children and a cross-sectional survey of physicians’ views on ARV palatability in which 50% disliked the taste of RTV liquid.26 Our palatability survey was based exclusively upon caregiver report and may have underestimated the proportion of children disliking the taste of RTV.

In conclusion, RTV-boosted ATV powder with optimized dual NRTI therapy in children ≥3 months to <11 years had an adequate overall rate of virologic suppression at week 24, which was maintained at week 48. The combination was highly acceptable to caregivers and was generally safe and well tolerated, regardless of prior ARV experience. No new safety concerns were identified, and no major PI substitutions associated with ATV phenotypic resistance were reported. Although LPV + RTV has established efficacy in young children, additional ARV formulations are needed for children requiring other options because of resistance, toxicity, tolerability (eg, taste) or adherence issues. ATV powder is an option for children unable to swallow pills, and for those who can, both powder and capsule ATV formulations facilitate a once-daily regimen when combined with solid NRTI formulations.2

These findings, along with those from the PRINCE-1 study, support using RTV-boosted ATV powder as a new treatment option for children aged ≥3 months to <11 years.

Back to Top | Article Outline

ACKNOWLEDGMENTS

The authors thank Benjamin Dale and Julian Martins of inScience Communications, Springer Healthcare, who provided medical writing support funded by Bristol-Myers Squibb.

Back to Top | Article Outline

REFERENCES

1. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. 2016. 2nd ed. Geneva, Switzerland: WHO Press, World Health Organization; Available at: http://www.who.int/hiv/pub/arv/arv-2016/en/. Accessed September 1, 2016.
2. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2016. Washington, D.C: Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed September 1, 2016.
3. Bristol-Myers Squibb Company. Prescribing Information for REYATAZ® (Atazanavir). 2015. Available at: http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed September 13, 2016.
4. Bristol-Myers Squibb Pharma EEIG. REYATAZ® (Atazanavir): EPAR – Product Information. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_All_Authorised_presentations/human/000494/WC500056382.pdf. Accessed November 8, 2016.
5. Medicines Patent Pool Foundation. MPP Licence for Atazanavir (ATV). Available at: http://www.medicinespatentpool.org/mpp-licence-on-atazanavir-atv/. Accessed January 20, 2016.
6. Janssen Pharmaceuticals Inc. PREZISTA® (Darunavir) Full Prescribing Information. 2014. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf#zoom=100. Accessed September 4, 2014.
7. ViiV Healthcare. Prescribing Information for Fosamprenavir (Telzir®). 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021548s021,022116s005lbl.pdf. Accessed September 4, 2014.
8. Abbott Laboratories. Prescribing Information for Kaletra. 2013. Available at: http://www.rxabbvie.com/pdf/kaletratabpi.pdf. Accessed September 4, 2014.
9. Medicines Patent Pool Foundation. The Medicines Patent Pool (MPP) Signs Licensing Agreement with AbbVie for HIV Paediatric Formulations of Lopinavir and Ritonavir. Available at: http://www.medicinespatentpool.org/mpp-signs-licensing-agreement-with-AbbVie-for-HIV-paediatric-formulations-of-lopinavir-and-ritonavir/. Accessed December 1, 2014.
10. US Food and Drug Administration. Lopinavir and Ritonavir Oral Pellets, 40 mg/10 mg. Tentative approval letter. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.pdf. Accessed March 11, 2016.
11. Kiser JJ, Rutstein RM, Samson P, et alAtazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25:1489–1496.
12. Rutstein RM, Samson P, Fenton T, et alPACTG 1020A Study Team. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the Pediatric AIDS Clinical Trials Group Protocol 1020A. Pediatr Infect Dis J. 2015;34:162–167.
13. Strehlau R, Donati AP, Arce PM, et alPRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.
14. Hong Y, Kowalski KG, Zhang J, et alModel-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents Chemother. 2011;55:5746–5752.
15. US Food and Drug Administration. Supplement Approval for Reyataz® (atazanavir). 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/206352Orig1s003,021567Orig1s038ltr.pdf. Accessed December 1, 2015.
16. European Medicines Agency. Guideline on the Clinical Development of Medicinal Products for the Treatment of HIV Infection. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/09/WC500150733.pdf. Accessed January 7, 2016.
17. Burger DM, Agarwala S, Child M, et alEffect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents Chemother. 2006;50:3336–3342.
18. Johnson M, Grinsztejn B, Rodriguez C, et al96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS. 2006;20:711–718.
19. Molina JM, Andrade-Villanueva J, Echevarria J, et alCASTLE Study Team. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323–332.
20. Daar ES, Tierney C, Fischl MA, et alAIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154:445–456.
21. Zhang D, Chando TJ, Everett DW, et alIn vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005;33:1729–1739.
22. Molina JM, Andrade-Villanueva J, Echevarria J, et alCASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646–655.
23. DeJesus E, Rockstroh JK, Henry K, et alGS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379:2429–2438.
24. Lennox JL, Landovitz RJ, Ribaudo HJ, et alACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461–471.
25. Musiime V, Fillekes Q, Kekitiinwa A, et alThe pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in African HIV-infected children. J Acquir Immune Defic Syndr. 2014;66:148–154.
26. Lin D, Seabrook JA, Matsui DM, et alPalatability, adherence and prescribing patterns of antiretroviral drugs for children with human immunodeficiency virus infection in Canada. Pharmacoepidemiol Drug Saf. 2011;20:1246–1252.
Keywords:

atazanavir powder; pediatric HIV infection; ritonavir

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.