Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 Week results

Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
AIDS (London, England) (Impact Factor: 5.55). 01/2008; 22(2):249-55. DOI: 10.1097/QAD.0b013e3282f2be1d
Source: PubMed

ABSTRACT To investigate pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r)-based therapy in HIV-1-infected infants 6 weeks to 6 months of age.
A prospective, multicenter, open-label trial of 21 infants with HIV-1 RNA > 10 000 copies/ml and treated with LPV/r 300/75 mg/m twice daily plus two nucleoside reverse transcriptase inhibitors. Intensive pharmacokinetic sampling was performed at 2 weeks and predose concentrations were collected every 8 weeks; safety and plasma HIV-1 RNA were monitored every 4-12 weeks for 24 weeks.
Median age at enrollment was 14.7 weeks (range, 6.9-25.7) and 19/21 completed > or= 24 weeks of study. Although LPV/r apparent clearance was slightly higher than in older children, the median area under the concentration-time curve 0-12 h (67.5 mug.h/ml) was in the range reported from older children taking the recommended dose of 230/57.5 mg/m. Predose concentrations stabilized at a higher level after the first 2 weeks of study. In as-treated analysis at week 24, 10/19 (53%) had plasma HIV-1 RNA < 400 copies/ml (median change, -3.33 log10 copies/ml); poor adherence contributed to delayed viral suppression, which improved with longer follow-up. Three infants (14%) had transient adverse events of grade 3 or more that were possibly related to study treatment but did not require permanent treatment discontinuation.
Despite higher clearance in infants 6 weeks to 6 months of age, a twice daily dose of 300/75 mg/m LPV/r provided similar exposure to that in older children, was well tolerated and provided favorable virological and clinical efficacy.

Download full-text


Available from: Jorge Andrade Pinto, Sep 27, 2015
14 Reads
  • Source
    • "Children with HIV infection carry with them a whole host of innate and external factors that can contribute to the development of HIV drug resistance mutations. First of all, infants who are perinatally infected with HIV often have extremely high VLs initially, which take longer to suppress than those in older children or adults, even when on fully active cART regimens.9–11 The pharmacokinetics of many ARVs in the setting of prematurity and early infancy are unknown or unpredictable, making appropriate dosing of these drugs difficult at times. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric patients infected with human immunodeficiency virus (HIV) are now living longer, healthier lives due to the advent of combined antiretroviral (ARV) therapy, including regimens that often contain non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, first-generation NNRTIs such as nevirapine (NVP) and efavirenz (EFV) have a low genetic barrier to resistance, and both drugs can become ineffective with a single viral point mutation. New agents with activity against resistant viral strains must be available to salvage children and adolescents with virologic failure after NNRTI use. One such drug, etravirine, an oral second-generation NNRTI approved for use in the US in heavily treatment-experienced HIV-1-infected adults in 2008, is accumulating data in this younger population. Etravirine became approved by the US Food and Drug Administration in early 2012 to be used in combination with other ARV medications in HIV-1-infected children aged 6 years to <18 years who are failing their regimens with HIV-1 strains resistant to NNRTIs and other ARVs. This approval was largely based on data from a prospective, open-label, phase II clinical trial in this age group prescribed etravirine at 5.2 mg/kg twice daily (up to the adult dose of 200 mg twice daily) in combination with an investigator-selected optimized background regimen. Currently available 48-week follow-up data show complete viral suppression (<50 copies/mL) in 56% of the patients, with relatively few serious adverse events attributed to the drug. Additional studies and case reports from the field suggest its utility in clinical practice. This review is designed to increase the background understanding of this drug in pediatric HIV providers, to lay out the current pediatric data to support its use, and to define its practical role in the treatment of HIV-infected children now and in the future.
    HIV/AIDS - Research and Palliative Care 04/2013; 5:67-73. DOI:10.2147/HIV.S32324
  • Source
    • "A smaller cohort of 21 infants aged 7 to 26 weeks treated with LPV/r (300/75 mg/m2 twice daily) plus 2 NRTI confirmed these encouraging findings [19]. Tolerance was good with six grade 3 adverse events occurring in three children possibly related to HAART: asymptomatic serum/sodium disturbances in two infants that resolved with disruption of therapy for 0–2 weeks and did not recur thereafter, and alanine aminotransferase elevation that did not recur after treatment suspension for 3 days. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. Methods: The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms.HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants.The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks. Discussion: This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies.
    BMC Infectious Diseases 10/2012; 12(1):246. DOI:10.1186/1471-2334-12-246 · 2.61 Impact Factor
  • Source
    • "However, ritonavir (RTV) as a single PI (sPI) was initially used for infants below six months of age and also when rifampicin was needed for co-treatment of tuberculosis, or in some children receiving therapy before the national roll-out guidelines were formulated. The correct dosage for LPV/r in infants below six months of age was established only in 2007 and the boosting of LPV/r with additional RTV when using rifampicin in 2008 [1,2]. Until then, many children were therefore treated with RTV sPI. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The historic use of full-dose ritonavir as part of an unboosted protease inhibitor (PI)-based antiretroviral therapy regimen in some South African children contributes to the frequent accumulation of major PI resistance mutations. In order to describe the prevalence of major PI resistance in children failing antiretroviral therapy and to investigate the clinical, immunological and virological outcomes in children with PI resistance, we conducted a cross-sectional study, with a nested case series, following up those children with major PI resistance. The setting was public health sector antiretroviral clinics in the Western Cape province of South Africa, and the subjects were children failing antiretroviral therapy. The following outcome measures were investigated: CD4 count, viral load and resistance mutations. Fourteen (17%) of 82 patients, referred from tertiary hospitals, had major PI resistance. All these patients were exposed to regimens that included ritonavir as a single PI. Immune reconstitution and clinical benefit were achieved when using a lopinavir/ritonavir-based treatment regimen in these children with prior PI resistance. At first HIV-1 viral load follow up after initial resistance testing (n = 11), only one patient had a viral load of less than 400 copies/ml; at a subsequent follow up (n = 9), the viral loads of five patients were less than 400 copies/ml. Patients retained on LPV/r had lower viral loads than those switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, two of three patients with follow-up resistance tests accumulated additional PI resistance. In children with pre-existing PI resistance, although initially effective, the long-term durability of a lopinavir/ritonavir-based treatment regimen can be compromised by the accumulation of resistance mutations. Furthermore, a second-line NNRTI regimen is often not durable in these patients. As genotypic resistance testing and third-line treatment regimens are costly and limited in availability, we propose eligibility criteria to identify patients with high risk for resistance and guidance on drug selection for children who would benefit from third-line therapy.
    Journal of the International AIDS Society 11/2011; 14(55):55. DOI:10.1186/1758-2652-14-55 · 5.09 Impact Factor
Show more