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  • 1
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    Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial
    Oxford University Press (OUP) ; 2020
    In:  Journal of Antimicrobial Chemotherapy Vol. 75, No. 3 ( 2020-03-01), p. 628-639
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 75, No. 3 ( 2020-03-01), p. 628-639
    Abstract: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0–24 and C24 with time to virological failure was evaluated by Cox regression. Results Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C & gt;T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P & lt;0.001). No significant relationship was demonstrated between darunavir AUC0–24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53–9.80), P=0.269; and 1.82 (0.61–5.41), P=0.279, respectively]. Conclusions Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkz479
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1467478-6
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  • 2
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    A Virological Benefit from an Induction/Maintenance Strategy: The Forte Trial
    SAGE Publications ; 2007
    In:  Antiviral Therapy Vol. 12, No. 1 ( 2007-01), p. 47-54
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 12, No. 1 ( 2007-01), p. 47-54
    Abstract: To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug anti-retroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients. Design Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24–32 weeks until plasma HIV RNA viral load (VL) ≤50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL 〉 50 copies/ml at 32 (and 24) weeks or subsequent rebound to 〉 400 copies/ml. Results 122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64–145). 52% were asymptomatic; median CD4 + T-cell count was 160x10 6 /l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500–241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P=0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log 10 copies/ml greater in the IM arm ( P=0.02). There were no significant differences between the two arms in the change in CD4 + T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm. Conclusions Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350701200101
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2007
    detail.hit.zdb_id: 2118396-X
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  • 3
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    HIV Drug Resistance Testing: Is the Evidence Really There?
    SAGE Publications ; 2004
    In:  Antiviral Therapy Vol. 9, No. 5 ( 2004-07), p. 641-648
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 9, No. 5 ( 2004-07), p. 641-648
    Abstract: To assess the strength of evidence supporting the routine use of HIV drug resistance testing. Design A critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials. Results Two cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3–11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies. Conclusions The available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350400900511
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
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  • 4
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    Online Resource
    A Randomized Controlled Trial of Genotypic HIV Drug Resistance Testing in HIV-1-Infected Children: The Pera (Penta 8) Trial
    SAGE Publications ; 2006
    In:  Antiviral Therapy Vol. 11, No. 7 ( 2006-10), p. 857-868
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 11, No. 7 ( 2006-10), p. 857-868
    Abstract: To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. Methods Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA 〉 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype TM ) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. Results One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing ( n=87) or no testing ( n=83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4 + T-cell percentage were 4.7 log 10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log 10 copies/ml in the RT arm and 1.23 in the NT arm ( P=0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P=0.9). Conclusion In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350601100711
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2006
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  • 5
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    Online Resource
    Evolution of Antiretroviral Phenotypic and Genotypic Drug Resistance in Antiretroviral-Naive HIV-1-Infected Children Treated with Abacavir/Lamivudine, Zidovudine/Lamivudine or Abacavir/Zidovudine, with or without Nelfinavir (The Penta 5 Trial)
    SAGE Publications ; 2002
    In:  Antiviral Therapy Vol. 7, No. 4 ( 2002-05), p. 293-303
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 7, No. 4 ( 2002-05), p. 293-303
    Abstract: To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with ‘Virtual Phenotype’ interpretation). Results At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare. Conclusions Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350200700410
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2002
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