Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients.
This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits.
Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients.
Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.
[Show abstract][Hide abstract] ABSTRACT: In our large observational cohort, use of tenofovir disoproxil fumarate (n=344) was associated with a greater decline in renal function than was use of alternative nucleoside analogues (n=314). Other associations included a lower CD4 cell count, decreased renal function at baseline, and diabetes. The declines were modest and did not lead to greater rates of discontinuation of therapy.
[Show abstract][Hide abstract] ABSTRACT: Available evidence suggests that a number of important clinical events in individuals with HIV infection are related to mt dysfunction. Several factors may contribute to the development of these events and the tissue(s) in which the event occurs. Some individuals are likely to have important genetic predispositions for mt disease, which may be unmasked by the presence of HIV infection or the introduction of NRTI antiretrovirals. HIV infection per se is associated with reduction in mtDNA content and changes in mt morphology and function, which in some cases leads to clinical events such as myopathy or peripheral neuropathy. NRTI antiretrovirals may impact mtDNA content and function through a number of different mechanisms and have been demonstrated to be causative of a number of clinical toxicities. In in vitro and in clinical studies, newer nucleoside and nucleotides agents such as lamivudine, emtricitabine, abacavir and tenofovir appear to be much weaker inhibitors of mtDNA polymerase-gamma or other mt functions, and appear to be associated with a lower risk of events thought to be related to mt toxicity. Simple, non-invasive tests for mt function are not available at present in the clinical routine, and assays of mtDNA content in blood cells may miss key aspects of mt function, require careful sample handling and may not reflect events occurring in other tissues. There remains a need for the development of rapid, cheap and clinically applicable assays that would enable the prediction of increased likelihood of mt events.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 muM (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naive and PI-experienced patients with HIV.
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