Pharmacology Update
Efavirenz
By William T. Elliott, MD, and James Chan, PharmD, PhD
The complexity of multidrug hiv regimens has proved to be a significant problem for HIV-infected individuals and their doctors—both in the timing of pill taking and the sheer number of pills. Now, Dupont pharmaceuticals has introduced the first once-daily anti-HIV drug. Efavirenz (Sustiva-DuPont), the third non-nucleoside reverse transcriptase inhibitor (NNRTI) on the market, was approved in September and joins nevirapine and delavirdine.
NNRTs inhibit HIV-1 activity by noncompetitive inhibition of reverse transcriptase—the enzyme responsible for the replication of the HIV virus. These antiviral agents differ in their mechanism of action from nucleoside reverse transcriptase inhibitors such as zidovudine, lamivudine, stavudine, and the newly approved abacavir, and protease inhibitors, such as indinavir, ritonavir, saquinavir, and nelfinavir.
Indications
Efavirenz is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Dosing Information
The recommended dosage for adults is 600 mg once daily in combination with a protease inhibitor and/or nucleoside reverse transcriptase inhibitors. For pediatric patients (£ 3 years of age weighing between 10 and 40 kg), the dose ranges from 200 mg to 400 mg once daily. The drug may be taken without regard to meals; however, a high-fat meal may increase the absorption of efavirenz and should be avoided.1 Efavirenz is supplied as 50 mg, 100 mg, and 200 mg capsules. Patients should be advised to store the capsules at 77°F with excursions permitted to 59-86°F.1
Potential Advantages
Efavirenz has a long elimination half-life (40-55) hours and is dosed once daily. Efavirenz with zidovudine/lamivudine (Combivir) is the most simple of the three-drug regimens (qd for efavirenz and bid for Combivir, total 5 pills per day). In a open-label trial, there were greater numbers of patients who discontinued indinavir (800 tid) + zidovudine (300 mg bid) + lamivudine (150 mg bid) due predominately to adverse events, compared to those discontinuing efavirenz (600 mg qd) + zidovudine (300 mg bid) + lamivudine (150 mg bid).1,2 The discontinuation rates were 36.4% (56/154) and 21.6% (32/148), respectively. Efavirenz penetrates the CNS, and the concentration of efavirenz in the cerebrospinal fluid is approximately three-fold that of the free (nonprotein-bound) fraction of drug in the plasma.1
Potential Disadvantages
Rapid emergence of resistant HIV-1 strains, which are cross-resistant to other NNRTs, have been observed in vitro.1 Like other NNRTs, drug interactions involving the cytochrome P450 system can be problematic. Efavirenz is both an inhibitor and inducer of CYP3A4 and an inhibitor of isoenzymes 2C9 and 2C19.1
Efavirenz should not be coadministered with astemizole, triazolam, midazolam, cisapride, or ergot derivatives.1 Coadministration with indinavir would require a dose increase from 800 mg to 1000 mg every eight hours.1 Efavirenz decreases the plasma levels of saquinavir, and, thus, the latter should not be used as a sole protease inhibitor in combination with efavirenz. INR should be monitored if warfarin is coadministered with efavirenz.
Central nervous system symptoms occur in approximately 50% of patients taking efavirenz.1 These symptoms include dizziness, impaired concentration, delusions, depression, and/or drowsiness.1 Patients should be warned about potential additive effects with other CNS depressants and cautioned against driving and operating machinery if patients experience these symptoms. As with other NNRTs, rash has been reported. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two weeks after initiation of therapy (median time, 11 days). Rash associated with blistering, moist desquamation, or ulceration occurred in 1% of adult patients (n = 455) compared to 3.5% in children (n = 57). The incidence of serious rash (e.g., erythemia multiforme, Steven-Johnson Syndrome, toxic epidermal necrolyis) was reported in 3.5% of children taking efavirenz.1 In general, rash was more common and of greater severity in children.1 Due to potential for fetal damage, efavirenz should be avoided in pregnant women.1
Comments
The FDA approved Efavirenz in September after a two month review. Similar to other agents, approval was based on changes in HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. The primary end point was the percent of patients with plasma HIV-RNA less than 400 copies/mL using the Roche RT-PCR HIV-1 assay.1 Study details are only available in abstract form, review article, or provided in the product information.1,2,3,7,8 These suggest that efavirenz in combination with zidovudine and lamivudine was at least as effective as indinavir with zidovudine and lamivudine or efavirenz and indinavir in antiretrovial naive patients (n = 450).1,2 These patients had an average CD4 cell count of 345 cells/mm3 and a mean HIV-RNA plasma level of 4.77 log10 copies/mL. The higher discontinuation rate of the protease inhibitor three-drug combination actually made the efavirenz three-drug combination appear more effective based on intent-to-treat analysis.7 At 36 weeks, the results favored the efavirenz combination with 66% of the patients achieving RNA less than 50 copies/mL (using ultrasensitive assay) compared to 50% for the indinavir regimen.7,8 The addition of efavirenz to a three-drug combination was reported to be more effective than a three-drug combination (indinavir + 2 NRTIs) in NRTI experienced but PI and NNRTI-naïve patients (mean RNA baseline copies > 4.39 log10 copies/mL).3 At 24 weeks, viral load reductions were 2.3 log10 and 1.6 log10 and 54% and 37% with RNA less than 50 copies/mL, respectively.3,8 As with all previous antiretroviral agents, emergence of resistance can be rapid with monotherapy. Also similar with other NNRTs, drug interaction and rash can be problematic. Long-term effectiveness and safety of efavirenz remain to be determined. Efavirenz is priced similar to the protease inhibitors, at $329 per month.
Clinical Implications
Efavirenz offers another alternative antiretroviral agent for the management of HIV-1 infection. There does not appear to be cross resistance between efavirenz and protease inhibitors. Zidovudine-resistant strains derived clinically have retained susceptibility to efavirenz.1 As with other antiretroviral agents, monotherapy with efavirenz promotes the rapid emergence of resistant virus. Efavirenz must be used in combination with other agents and should not be added as a sole agent to a failing regimen.
The Department of Health and Human Services, The International AIDS Society, and The British HIV Association published guidelines for antiretrovial therapy in 1998.4,5,6 The current standard is to initiate therapy with one or two protease inhibitors with two NRTIs. The weight of the clinical data supports a regimen of a protease inhibitor with two NRTIs. NNRTIs, such as efavirenz, offer a potential alternative to a protease inhibitor. These can be used with two NRTIs with or without a protease inhibitor. Recently, the Department of Health and Human Services updated their earlier guidelines and considered efavirenz the preferred NNRTI, citing its comparable viral suppression activity to indinavir.9 The initial antiretrovial regimen is no doubt the most critical one for the course of the disease. Factors to consider when initiating therapy are viral load, CD4 cells, potential drug toxicities, drug interactions, and the patient’s willingness to commit to adhering to the complex drug regimens. Efavirenz’s once-daily dosing may offer an advantage over other antiretrovirals in reducing regimen complexity. Early initiation of treatment appears to be associated with virologic, immunologic, and clinical benefit.4 Treatment should be supervised by an expert in HIV therapy.
References
1. Sustiva Product Information. DuPont Pharmaceutical. September 1998.
2. Staszewski S, et al. 12th World AIDS Conference, Geneva, Switzerland, June 28-July 3, 1998. Abstract.
3. Fessel WJ, et al. 12th World AIDS Conference, Geneva, Switzerland, June 30, 1998. Abstract.
4. DHHS—Panel on Clinical Practices for the Treatment of HIV Infection. Ann Intern Med 1998;128:1079-1100.
5. International AIDS Society—USA Panel. JAMA 1998;380:78-86.
6. British HIV Association. Lancet 1998;352:314-316.
7. Morales-Ramirez J, et al. Int Sci Conf Antimicrob Agents Chemother 1998;38:394. Abstract I-103.
8. Adkins JC, et al. Drugs 1998;56(6):1055-1064.
9. http://www.hivatis.org
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