Combination Of Efavirenz Research Articles

Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients.

Limited information exists on the clinical usefulness of drug level monitoring for efavirenz, a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI). The aim of this study was to determine whether efavirenz plasma concentration monitoring could predict treatment failure and central nervous system (CNS) tolerability. Blood samples were obtained from 130 HIV-infected patients receiving efavirenz in combination with other antiretroviral agents for more than 3 months. Efavirenz plasma concentrations were measured by high-performance liquid chromatography. An evaluation of CNS side-effects was performed and the viral load, CD4 cell count and other clinical and laboratory data were assessed. In 85 patients, these measures were repeated at 3 month intervals. Efavirenz plasma levels (n = 226) were measured at an average of 14 h after drug intake. Drug concentrations ranged from 125 to 15230 microg/l (median 2188). Large inter-patient (CV 118%) and limited intra-patient (CV 30%) variabilities were observed in efavirenz levels. Virological failure was observed in 50% of patients with low efavirenz levels (< 1000 microg/l) versus 22 and 18% in patients with 1000-4000 microg/l or more than 4000 microg/l, respectively. CNS toxicity was approximately three times more frequent in patients with high efavirenz levels (> 4000 microg/l) compared with patients with 1000-4000 microg/l. Treatment failure and CNS side-effects are associated with low and high efavirenz plasma levels, respectively. The important inter-individual variability in efavirenz levels strongly argues for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment.

Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy.

Efavirenz is a potent and selective nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Nucleotide sequence analyses of the protease and RT genes (coding region for amino acids 1 to 229) of multiple cloned HIV-1 genomes from virus found in the plasma of patients in phase II clinical studies of efavirenz combination therapy were undertaken in order to identify the spectrum of mutations in plasma-borne HIV-1 associated with virological treatment failure. A K103N substitution was the HIV-1 RT gene mutation most frequently observed among plasma samples from patients for whom combination therapy including efavirenz failed, occurring in at least 90% of cases of efavirenz-indinavir or efavirenz-zidovudine (ZDV)-lamivudine (3TC) treatment failure. V108I and P225H mutations were observed frequently, predominantly in viral genomes that also contained other nonnucleoside RT inhibitor (NNRTI) resistance mutations. L100I, K101E, K101Q, Y188H, Y188L, G190S, G190A, and G190E mutations were also observed. V106A, Y181C, and Y188C mutations, which have been associated with high levels of resistance to other NNRTIs, were rare in the patient samples in this study, both before and after exposure to efavirenz. The spectrum of mutations observed in cases of virological treatment failure was similar for patients initially dosed with efavirenz at 200, 400, or 600 mg once a day and for patients treated with efavirenz in combination with indinavir, stavudine, or ZDV-3TC. The proportion of patients carrying NNRTI resistance mutations, usually K103N, increased dramatically at the time of initial viral load rebound in cases of treatment failure after exposure to efavirenz. Viruses with multiple, linked NNRTI mutations, especially K103N-V108I and K103N-P225H double mutants, accumulated more slowly following the emergence of K103N mutant viruses.

EFAVIRENZ IN THE MANAGEMENT OF HIV INFECTION

SUMMARYEfavirenz, which is likely to be licensed in the UK and throughout Europe shortly, represents a major advance in the treatment of HIV infection. It belongs to the non‐nucleoside reverse transcriptase (NNRTI) class of drugs and, as such, it should only be prescribed with other potent therapies to avoid the development of resistance. However, in the pivotal head‐to‐head comparison of efavirenz with lamivudine and zidovudine, treatment over a 24‐week period proved superior to treatment with a standard regimen containing indinavir. The results from prolonged follow‐up of this study are eagerly awaited but it is clear that a combination of efavirenz with nucleoside analogues provides a potent proteinase inhibitor‐sparing regimen which may have less toxicity. Additional data also indicate that the combination of a proteinase inhibitor (indinavir) with efavirenz provides an extremely potent regimen which is well tolerated and produces complete inhibition of plasma HIV viraemia over prolonged periods of follow‐up. In common with many other currently available potent anti‐HIV therapies, the optimum use of this drug is being determined by ongoing clinical studies but it is clear that ease of administration (once‐daily), freedom from serious side‐effects and potency when used in combination are likely to represent a very considerable advance in the management of HIV infection.

Efavirenz offers new options in HIV infection

Results from a landmark clinical study show that efavirenz [DMP 266; DuPont Merck], a potent and selective non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), is a valuable new anti-HIV agent, allowing effective suppression of viral load while sparing the early use of protease inhibitors in patients starting antiretroviral therapy. In Dupont Pharmaceuticals Study 006, the use of efavirenz in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) suppressed viral load to undetectable levels in a greater percentage of patients compared with a currently used standard regimen of 2 NRTIs and a protease inhibitor, delegates were told at the 12th World AIDS Conference [ Geneva, Switzerland; June 1998 ].

Efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.