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.
"Figure 1 shows that (as expected) we observe a time-dependent increase in the appearance of HIV-1 pol DNA indicative of cell-cell spread within the control sample that was incubated in the absence of PI (Figure 1A and B). Notably, cell-to-cell spread of HIV-1 was potently blocked in the presence of both Lopinavir and Darunavir at doses corresponding to the maximum plasma concentrations (Cmax) (14 μM LPV; 12 μM DRV) achieved in vivo[35-37], with no increase in HIV-1 DNA detected during co-culture in the presence of drug (Figure 1A and B). Inhibiting de novo synthesis of reverse transcripts by blocking cell-to-cell spread would also be expected to impact on the appearance of 2-LTR circles that are used as a marker of HIV-1 nuclear import a step that immediately precedes proviral integration . "
[Show abstract][Hide abstract] ABSTRACT: The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. Recently it has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Protease Inhibitors (PIs) constitute an important component of ART; however whether this class of inhibitors can suppress cell-to-cell transfer of HIV-1 is unexplored. Here we have evaluated the inhibitory effect of PIs during cell-to-cell spread of HIV-1 between T lymphocytes.
Using quantitative assays in cell line and primary cell systems that directly measure the early steps of HIV-1 infection we find that the PIs Lopinavir and Darunavir are equally potent against both cell-free and cell-to-cell spread of HIV-1. We further show that a protease resistant mutant maintains its resistant phenotype during cell-to-cell spread is transmitted more efficiently than wild-type virus in the presence of drug. By contrast we find that T cell-T cell spread of HIV-1 is 4-20 fold more resistant to inhibition by the RTIs Nevirapine, Zidovudine and Tenofovir. Notably, varying the ratio of infected and uninfected cells in co-culture impacted on the degree of inhibition, indicating that the relative efficacy of ART is dependent on the multiplicity of infection.
We conclude that if the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV-1 spread.
[Show abstract][Hide abstract] ABSTRACT: Darunavir is the result of wide and in-depth investigation into HIV protease inhibitors (PIs). This drug is a non-peptide PI, with a distinct chemical structure that, by conferring it drug with enhanced binding affinity and a slower dissociation rate, makes it more potent than the remaining PIs developed to date.
Because of its pharmacokinetic characteristics, darunavir must be coadministered with low doses of ritonavir. Furthermore, these characteristics allow oral administration (preferably with meals), once-daily administration in non-resistant HIV strains, and a less complicated treatment regimen with improved convenience in highly varied contexts, including mild-to-moderate renal and hepatic impairment.
The potential of darunavir for pharmacological interactions is highly acceptable and this drug can be administered without dose adjustments with almost all antiretroviral agents except maraviroc, lopinavir, saquinavir and tipranavir. There are no problems of pharmacodynamic antagonism with any of these drugs.
Cytotoxic doses are well above therapeutic doses, providing a wide safety margin.
The spectrum of action is very wide, and darunavir is effective against all subtypes of HIV-1 and against HIV-2 and acts well in mononuclear and monocyte/macrophage cell lines. Darunavir is also active against most HIV strains resistant to the remaining PIs and the robustness of this drug against the known mechanisms of resistance of HIV is also superior to that of the other available PIs. Consequently, the induction and selection of mutations conferring resistance to this drug may be slower and more difficult, resulting in its antiviral effect remaining unchanged for prolonged periods.
[Show abstract][Hide abstract] ABSTRACT: As antiretroviral therapy scale-up proceeds in developing countries, simple and inexpensive procedures are required to monitor the prevalence and transmission of drug-resistant HIV strains to ensure optimal use of antiviral therapy. This article reviews new surveillance methods and practices used to monitor drug resistance in the developing world.
Several recently published studies report the successful development of methods using dried blood spots, collected on filter paper, for HIV drug resistance genotyping tests. In concert to antiretroviral therapy rollout, the WHO has developed a laboratory network and sought to implement surveillance of transmitted drug resistance in developing countries. A small number of developing world prevalence studies have thus far been published using dried blood spots. These studies reveal low rates of transmitted drug resistance. Other studies indicate that the use of dried blood spots for HIV drug resistance surveillance may possibly lead to overestimates.
The use of dried blood spots as a method of specimen collection and storage is simple, inexpensive and is an appropriate technique for the surveillance of transmitted HIV drug resistance.
Current Opinion in Infectious Diseases 01/2009; 21(6):653-8. DOI:10.1097/QCO.0b013e3283186d1a · 5.01 Impact Factor
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