Pharmacokinetics of High-Dose Lopinavir-Ritonavir with and without Saquinavir or Nonnucleoside Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pediatric and Adolescent Patients Previously Treated with Protease Inhibitors

Robbins, Brian L.; Capparelli, Edmund V.; Chadwick, Ellen G.; Yogev, Ram; Serchuck, Leslie; Worrell, Carol; Smith, Mary E.; Alvero, Carmelita; Fenton, Terence; Heckman, Barbara; Pelton, Stephen I.; Aldrovandi, Grace M.; Borkowsky, William; Rodman, John H.; Havens, Peter L.

doi:10.1128/aac.00224-08

Cited by 22 publications

(14 citation statements)

References 41 publications

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“…(16) Another study from South Africa also demonstrated a good virologic response in children on continued LPV/r therapy, despite the presence of LPV resistance, when compared to patients who switched to an NNRTI regimen. (17) The residual benefit could be due to the high inhibitory quotient of LPV/r (18) (requiring multiple mutations to prevent resistance) and the beneficial effect of continuous drug pressure on selecting less-fit viral variants. (19) However the response rate to LPV/r in patients with PI resistance is inferior to DRV/r or TPV/r.…”

Section: Discussionmentioning

confidence: 99%

Virologic Failure Among Children Taking Lopinavir/Ritonavir-containing First-line Antiretroviral Therapy in South Africa

Meyers

Sawry

Wong

et al. 2015

Pediatric Infectious Disease Journal

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Objective To report the outcomes, clinical management decisions and results of resistance testing among a group of children who developed virologic failure on first line lopinavir/ritonavir (LPV/r)-based therapy from a large cohort of ART-treated children in Soweto. Design Historical cohort study Methods Children with virologic failure were identified from a group of 1692 children <3 years who had initiated first-line LPV/r-containing therapy since 2000 up to end November 2011. Genotyping was conducted in some children and outcomes, management decisions and resistance results were described. Results 152 children with virologic failure on first-line LPV/r-containing ART were included. Resistance testing was performed in 75/152 (49%) and apart from a younger age (11.1 vs 15.1 months, p=0.04), the children with vs those without resistance testing were similar for baseline characteristics (weight, CD4, VL and time to failure). Genotyping revealed that 8/75 (10.7%) had significant LPV/r-associated resistance mutations, including 2 with intermediate DRV resistance. Among 63/75 (84%) children remaining on LPV/r-based therapy, 32/63 (51%) achieved virologic suppression, 2 of these children with significant LPV mutations. 12/152 (8%) children were switched to NNRTI-based therapy in accordance with local guidelines at the time. Of these, 4/12 (33%) resuppressed, and the rest did not achieve virologic suppression including the 2 with LPV mutations. Conclusions Virologic failure of LPV/r-containing first line regimens is associated with accumulation of LPV/r mutations in children. The implications are unclear and surveillance at selected sites is warranted for long-term virologic outcomes and development of resistance.

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Section: Discussionmentioning

confidence: 99%

Virologic Failure Among Children Taking Lopinavir/Ritonavir-containing First-line Antiretroviral Therapy in South Africa

Meyers

Sawry

Wong

et al. 2015

Pediatric Infectious Disease Journal

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“…Although they are less frequently used, some heavily pretreated children may benefit from dual PI combinations, such as LPV and SQV boosted with low‐dose RTV. In the above‐mentioned PATCG 1038 study, high‐dose LPV/r with or without SQV resulted in significant reductions in viral load and increases in CD4 cell counts at week 24 [35]. Long‐term dual therapy with standard dose LPV/r and SQV (HIV NAT‐017) has also been shown to produce significant immunological improvement and antiviral effect at week 48 [36].…”

Section: Introductionmentioning

confidence: 99%

Boosted protease inhibitors as a therapeutic option in the treatment of HIV‐infected children

Ramos

2009

HIV Medicine

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Objective Paediatric HIV treatment must address various special considerations. Administration of pharmacokinetically enhanced protease inhibitors (PIs) can improve paediatric therapeutic outcomes. The objective of this study was to review the use of boosted PI regimens in children. Methods Systematic literature searches of published manuscripts and conference databases using generic drug names and specific keywords were performed to ensure thorough and balanced reporting of available data. Results Boosted PI regimens offer multiple options across a range of ages and are efficacious in naı¨venaı¨ve and experienced children; safety and tolerability are similar to those observed in adults. Novel boosted PI simplification approaches may foster adherence and diminish resistance. Conclusions Boosted PIs are key components of first-and second-line treatments in children. Identifying factors associated with the response to highly active antiretroviral therapy in children may ultimately permit individualized therapies.

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“…The PK of abacavir were reported from the PACTG protocols P1018 and P1052;5,6 lamivudine and zidovudine data (including data on phosphorylation to the intracellular triphosphate metabolites) were collected in PACTG studies P1012 and P1052;7 lopinavir/ritonavir and saquinavir were studied in PACTG protocol P1038;8 and atazanavir was studied in PACTG protocol 1020A and in Adolescent Medicine Trials Network studies along with tenofovir 5,9. The PACTG protocol P1038 and the author’s study in children with experience of ARV suggested that the use of high doses of lopinavir/ritonavir might be required for salvage HIV therapy in adolescent patients 8,10. The Adolescent Medicine Trials Network study by Kiser et al evaluated the PK of the combined administration of atazanavir/ritonavir and tenofovir in young adults with HIV infection 9.…”

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confidence: 99%

Personalized Therapeutics: HIV Treatment in Adolescents

Rakhmanina

Capparelli

Anker

2008

Clin Pharmacol Ther

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Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends on multiple factors. The continued use of higher (weight-or surface-based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV-infected adolescents.Despite significant progress in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) infection, it was estimated that there were 2.3 million children under the age of 15 years with HIV infection in 2006.1 Among those, ~780,000 (600,000-1,000,000) were estimated to be in need of antiretroviral therapy (ART). In the United States and other developed countries, an increasing number of children with perinatally acquired HIV infection are now surviving into adolescence and adulthood. In addition, large numbers of American teenagers continue to acquire HIV infection through sexual contact and intravenous drug use; youths between 13 and 24 years of age account for 15% of the 40,000 new HIV cases per year.2 Based on the strengthening global response to the problem of HIV/AIDS in recent years, the number of adolescents receiving ART worldwide is rapidly increasing.3 Given the growing number of HIV-infected youth with access to ART, a better understanding of the disposition of antiretroviral (ARV) drugs during puberty is urgently needed. The selection of ART dosages for patients in the pubertal stages of maximal growth is left to the provider's discretion, and individual differences in the progression to sexual maturation are often not provided for. However, very few studies have investigated the PK/PD of ARV agents in adolescents and young adults. The PK of abacavir were reported from the PACTG protocols P1018 and P1052;5 , 6 lamivudine and zidovudine data (including data on phosphorylation to the intracellular triphosphate metabolites) were collected in PACTG studies P1012 and P1052;7 lopinavir/ritonavir and saquinavir were studied in PACTG protocol P1038;8 and atazanavir was studied in PACTG protocol 1020A and in Adolescent Medicine Trials Network studies along with tenofovir.5 , 9 The PACTG protocol P1038 and the author's study in children with experience of ARV suggested that the use of high doses of lopinavir/ritonavir might be required for salvage HIV therapy in adolescent patients.8 , 10The Adolescent Medicine Trials Network study by Kiser et al. evaluated the PK of the combined administration of atazanavir/ritonavir and tenofovir in young adults with HIV infection.9 A higher level of tenofovir exposure was expected on the basis of data from healthy volunteers, but this was not seen in HIV-infected subjects, most likely because of a faster tenofovir clearance, as apparent in the h...

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Pharmacokinetics of High-Dose Lopinavir-Ritonavir with and without Saquinavir or Nonnucleoside Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pediatric and Adolescent Patients Previously Treated with Protease Inhibitors

Cited by 22 publications

References 41 publications

Virologic Failure Among Children Taking Lopinavir/Ritonavir-containing First-line Antiretroviral Therapy in South Africa

Virologic Failure Among Children Taking Lopinavir/Ritonavir-containing First-line Antiretroviral Therapy in South Africa

Boosted protease inhibitors as a therapeutic option in the treatment of HIV‐infected children

Personalized Therapeutics: HIV Treatment in Adolescents

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