Pharmacologic aspects of new antiretroviral drugs.
ABSTRACT The biggest challenge facing highly antiretroviral-experienced patients and their caregivers is the diminishing number of therapeutic options available that sustain activity despite increasing numbers of drug-resistance mutations. New options in antiretroviral treatment have been introduced: two new members of traditional antiretroviral classes (darunavir and etravirine) and two drugs with novel mechanisms of action (raltegravir and maraviroc). Each was approved for use in treatment-experienced patients. A fifth drug-containing efavirenz, tenofovir, and emtricitabine (Atripla; Bristol-Myers Squibb, New York, NY, and Gilead Sciences, Foster City, CA)-is a novel coformulation of existing drugs from two different classes, simplifying administration with the intent of increasing adherence. Because successful management of HIV infection requires the simultaneous use of three or more drugs, understanding the pharmacologic aspects of coadministration is critical. This review summarizes the pharmacokinetic properties affecting the administration of these recently approved drugs in light of highly active antiretroviral treatment guidelines.
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ABSTRACT: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.Clinical Pharmacokinetics 02/2001; 40(12):893-905. · 6.11 Impact Factor
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ABSTRACT: Combination antiretroviral therapy with protease inhibitors has transformed HIV infection from a terminal condition into one that is manageable. However, the complexity of regimens makes adherence to therapy difficult. To assess the effects of different levels of adherence to therapy on virologic, immunologic, and clinical outcome; to determine modifiable conditions associated with suboptimal adherence; and to determine how well clinicians predict patient adherence. Prospective, observational study. HIV clinics in a Veterans Affairs medical center and a university medical center. 99 HIV-infected patients who were prescribed a protease inhibitor and who neither used a medication organizer nor received their medications in an observed setting (such as a jail or nursing home). Adherence was measured by using a microelectronic monitoring system. The adherence rate was calculated as the number of doses taken divided by the number prescribed. Patients were followed for a median of 6 months (range, 3 to 15 months). During the study period, 45,397 doses of protease inhibitor were monitored in 81 evaluable patients. Adherence was significantly associated with successful virologic outcome (P < 0.001) and increase in CD4 lymphocyte count (P = 0.006). Virologic failure was documented in 22% of patients with adherence of 95% or greater, 61% of those with 80% to 94.9% adherence, and 80% of those with less than 80% adherence. Patients with adherence of 95% or greater had fewer days in the hospital (2.6 days per 1000 days of follow-up) than those with less than 95% adherence (12.9 days per 1000 days of follow-up; P = 0.001). No opportunistic infections or deaths occurred in patients with 95% or greater adherence. Active psychiatric illness was an independent risk factor for adherence less than 95% (P = 0.04). Physicians predicted adherence incorrectly for 41% of patients, and clinic nurses predicted it incorrectly for 30% of patients. Adherence to protease inhibitor therapy of 95% or greater optimized virologic outcome for patients with HIV infection. Diagnosis and treatment of psychiatric illness should be further investigated as a means to improve adherence to therapy.Annals of internal medicine 08/2000; 133(1):21-30. · 13.98 Impact Factor
- Journal of Antimicrobial Chemotherapy 01/2008; 60(6):1409-10. · 5.34 Impact Factor