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    ABSTRACT: The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.
    Antiviral therapy 02/2005; 10(3):375-92. · 3.07 Impact Factor
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    ABSTRACT: The three main components of long-term efficacy for a combination of antiretrovirals are: (i) the strength of the antiviral effect, (ii) toxicity profile and (iii) patient acceptability of the regimen. Intent-to-treat (ITT) analysis, where discontinuations and switches are considered failures [ITT, switch equals failure (ITT/S = F)], is a regulatory standard for analysing the efficacy of antiretrovirals. A review of all clinical trials published in FDA product labels was conducted, including all clinical trials of boosted protease inhibitor- or nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in treatment-naive patients, and all clinical trials of antiretrovirals in treatment-experienced patients. Clinical trials where the results are presented in the standard ITT/S = F method were included. For randomized clinical trials in treatment-naive patients, the majority of treatment discontinuations have been either for toxicity (32%) or patient refusal of treatment (41%), with only 27% of failure endpoints for virological reasons among recent clinical trials in naive patients. Therefore, there is the potential for the results from ITT/S = F analysis to be driven by non-virological endpoints - a new treatment can be classified as 'more efficacious' than control owing to fewer discontinuations due to adverse events or patient preference. In order to understand the intrinsic potency of the antiretroviral regimen under study, ITT analysis needs to be supplemented by standardized as-treated analyses, excluding withdrawals for toxicity or other reasons. To evaluate the efficacy of a treatment strategy or sequential treatment regimens, the 'ITT, switch included' (ITT/SI) method: where changes from the initial randomized treatment are not classified as treatment failure - can be used. However, interpretation of clinical trials using ITT/SI analysis is difficult and depends on the frequency of treatment switching in the different arms of a trial. Conclusions on efficacy from clinical trials can depend on the primary analysis used; most commonly, treatments could be significantly different by ITT/S=F analysis, but then interpreted as equivalent using the ITT/SI or as-treated methods.
    Antiviral therapy 02/2005; 10(3):367-74. · 3.07 Impact Factor
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    ABSTRACT: A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance. Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n = 118) or ritonavir and saquinavir (400/400 mg twice daily; n = 115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA < or = 20 copies/ml after 48 weeks (missing value = failure). Patients remained under follow-up also in case of switch from the randomized therapy. At baseline, the median CD4 cell counts were 126 (range: 0-942) (nelfinavir/nevirapine) and 150 (0-642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3-6.4) in both groups. A total of 102 (86%) and 101 (88%) were antiretroviral-naive. 44% discontinued randomized therapy; P = 0.13. Of these, 80 and 73% switched therapy due to adverse events; P = 0.99. At week 48, 69 and 56%, respectively, had a HIV RNA < or = 20 copies/ml; P = 0.037. A regimen of nelfinavir/nevirapine had a favourable virological effect and tolerability over a 48-week period compared with ritonavir/saquinavir, when administered in combination with two nucleoside reverse transcriptase inhibitors. However, more extensive follow-up is required to determine the long-term consequences of triple class HAART regimens, including the development of broad drug resistance.
    Antiviral therapy 12/2003; 8(6):595-602. · 3.07 Impact Factor

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May 26, 2014