Search

Objectives: The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians use of resistance testing was examined. Methods: UTILIZE was an observational study conducted at 40 sites in the United States. Patients currently failing a PI-based regimen were randomized to receive either a genotype (GT) or combined phenotype-genotype test (PGT) and a treatment decision was made at the second study visit. Results: 246 patients enrolled, 236 had resistance test results, and 139 (59) had evidence of HIV-1 resistance to ≥1 PI. Among these 139 patients, more than 50 had viruses that remained sensitive to tipranavir and darunavir, whereas susceptibility to other PIs was markedly lower (<22). Increasing prior PI exposure was associated with reduced susceptibility to most ARV agents. After obtaining resistance test results, 83 of patients changed therapy. Newly available or investigational ARVs were used frequently. The reason investigators most often cited for changing therapy was the patient resistance test results (82) and the most common reason for not changing therapy was the inability to construct an active regimen. The majority of patients who exhibited PI resistance received two or more active agents in the new regimen. Conclusions: Overall, 59 of TEPs failing a PI-based regimen had HIV-1 with PI resistance. The majority of these patients viruses remained sensitive to either tipranavir or darunavir. Investigators used results from resistance assays to construct a new regimen, frequently with newer agents. In PI-experienced patients, tipranavir and darunavir remain the most likely available active PIs.

ABSTRACTNevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for ≥6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

ABSTRACTThe study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC50) for 80% of the dosing interval. At an amprenavir EC50of 0.03 μM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC50s are 0.05 and 0.08 μM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC50ratio of 5, the target attainment rates were similar. Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC50of 0.05 μM. Even at 0.12 μM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.

The introduction of HIV-1 protease inhibitors in 1995 ushered in the era of highly active antiretroviral therapy. For the first time, inhibition of two key enzymes responsible for HIV replication, reverse transcriptase and protease, was possible. The combination of two nucleoside reverse transcriptase inhibitors with a single protease inhibitor proved highly effective at reducing viral burden. In resource-rich countries where such combination therapy is readily available, dramatic reductions in HIV-related morbidity and mortality have been seen. However, long-term use of highly active antiretroviral therapy has led to several issues, including development of drug resistance and metabolic complications. Atazanavir (formerly BMS-232632), a novel azapeptide protease inhibitor, is a potent protease inhibitor that is not associated with significant dyslipidaemia as seen with other protease inhibitors. In this review, the current standard approach to the treatment of HIV in the US will be discussed as background to understand the potential utility of this new antiretroviral agent.

The correctional system presents unique challenges that can interfere with the HIV-infected inmate's ability to adhere to antiretroviral treatment. One mechanism to facilitate adherence is twice-daily dosing. This article compares safety and efficacy data on five currently available protease inhibitors - amprenavir, indinavir, nelfmavir, saquinavir soft gel capsules, and ritonavir - and examines their adaptability to twice-daily dosing. Movements toward once-daily dosing are discussed, as is the development of new dual protease inhibitor regimens. Simplified dosing strategies along with a comprehensive continuum of care have important benefits for adherence as well as for the inmate's long-term well-being.

The correctional system presents unique challenges that can interfere with the HIV-infected inmate’s ability to adhere to antiretroviral treatment. One mechanism to facilitate adherence is twice-daily dosing. This article compares safety and efficacy data on five currently available protease inhibitors - amprenavir, indinavir, nelfmavir, saquinavir soft gel capsules, and ritonavir - and examines their adaptability to twice-daily dosing. Movements toward once-daily dosing are discussed, as is the development of new dual protease inhibitor regimens. Simplified dosing strategies along with a comprehensive continuum of care have important benefits for adherence as well as for the inmate’s long-term well-being.

We studied patients with a n ew anterior uveitis syndrome associated with rifabutin use.

ABSTRACTFosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.

We describe a well-documented case of Eastern equine encephalitis (EEE) in a patient who presented with fever and altered mental status and who had focal cranial lesions that were evident on both computed tomography (CT) and magnetic resonance imaging. Only 15 CT scans performed for patients with EEE have been described previously; findings on most were normal or revealed diffuse cerebral edema. It is not widely appreciated that EEE can manifest as discrete lesions on CT. We review the radiographic experience with EEE and interpret it in light of certain clinical and pathological features of the disease.