Darunavir: pharmacokinetics and drug interactions.
ABSTRACT Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.
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ABSTRACT: Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full-length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future.PLoS Computational Biology 06/2013; 9(6):e1003103. · 4.87 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Surveillance for transmitted HIV drug resistance is essential to assessing the longer term sustainability and durability of first-line antiretroviral therapy (ART). Increases in pre-ART resistance would compromise the ability to achieve optimal and durable treatment outcomes using currently recommended antiretrovirals. RECENT FINDINGS: In the Asia region, many countries have conducted studies of transmitted resistance among recently HIV-infected and pre-ART patients. Data vary by methodology and resistance interpretation systems. Studies in some high-income settings have shown stabilizing or declining rates (e.g. Taiwan, Hong Kong), and increasing rates in others (e.g. Japan). In low-income and middle-income Asian countries, resistance has primarily been reported to be below WHO thresholds for moderate resistance (i.e. <5%). However, studies have identified an increased risk of resistance associated with male-to-male sex and/or higher rates among cohorts of MSM. Some countries still lack systematically collected transmitted resistance data. SUMMARY: To date, there does not appear to be a need for baseline resistance testing in most Asian settings for which there are data. However, MSM appear to be at higher risk of transmitted resistance and may benefit from enhanced resistance assessments and prevention interventions.Current opinion in HIV and AIDS 11/2012; · 4.75 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: This review provides an update of recent data on the development of HIV-1 drug resistance during treatment and its transmission in sub-Saharan Africa after the scale-up of antiretroviral therapy (ART). RECENT FINDINGS: Evidence is accumulating of a rising prevalence of transmitted HIV drug resistance (TDR), predominantly associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs), in east and southern Africa. Pretherapy resistance is associated with first-line therapy failure. Accumulation of resistance mutations during first-line failure can be prevented by early detection and timely switching to second-line ART. Important gaps in service delivery and programme performance, associated with resistance development, affect a considerable proportion of ART programmes, particularly with respect to inadequate supply systems and patient retention. The reduction in new HIV infections associated with earlier use of ART is predicted to outweigh the risk of increasing TDR. Future levels of TDR are estimated to be diminished by improving switching practices to second-line regimens. SUMMARY: TDR is on the rise after the recent scale-up of ART in Africa. To prevent the development and spread of drug resistance and sustain the effectiveness of ART programmes, there is a need to improve drug supply systems, patient retention and access to routine viral load monitoring. Enhanced resistance monitoring is warranted in Africa.Current opinion in HIV and AIDS 11/2012; · 4.75 Impact Factor