June 30, 1998
Poster Session 22386: A double-blind, placebo-controlled study to assess the safety, tolerability, and antiviral activity of efavirenz (EFV, Sustiva, DMP-266) in combination with open-label zidovudine (ZDV) and lamivudine (3TC) in HIV-1 infected patients [DMP 266-004]
One study compared the addition of efavirenz 400 mg qd or 600 mg qd or placebo to the combination of zidovudine plus lamivudine in patients who had been on that dual nucleoside regimen for a minimum of eight weeks. These patients had no prior NNRTI or protease inhibitor experience and had viral loads of > 2500 copies/mL. After four weeks of treatment more patients on the efavirenz 600 dose had viral loads < 400 copies/mL than those receiving 400 mg qd (69% vs. 53%). However, these viral load reductions were short lived. After 16 weeks of treatment only 33% (6/18) of patients on the high dose efavirenz arm, and 23% (5/22) of patients on the lower dose efavirenz arm maintained viral loads < 400 copies/mL. Over 60% of patients on either dose of efavienz experienced a CNS toxicity, most commonly headache, dizziness, or euphoria. Rash was seen in about 20% of efavirenz recipients. The CNS adverse events and rash were usually of mild severity and no patients discontinued participation for either of these toxicities.
This study illustrates the superior antiviral activity of the 600 mg qd dose of efavirenz compared to a lower dose. It also demonstrates that efavirenz should not be added as a single agent to a combination that is not already achieving maximal suppression of the patient's viral load. Doing so will often result in a short period of suppression of viral replication followed by the development of efavirenz resistance. This study also provides a good indication of the expected toxicity rates of efavirenz. The incidence of rash appears higher than some of the original reports, although it apprears to be milder than that experienced in patients on nevirapine, and seldom results in cessation of therapy.
Poster Session 22340: Initial effectiveness and tolerability of nelfinavir (NFV) in combination with efavirenz (EFV, Sustiva, DMP-266) in antiretroviral therapy naive or nucleoside analogue experienced HIV-1 infected patients: characterization in a phase II, open-label, multicenter study at 24 weeks [DMP 266-024]
Another study investigated the activity of efavirenz 600 mg qd plus nelfinavir 750 mg qd in antiretroviral naive patients or patients with nucleoside reverse transcriptase inhibitor experience. Approximately 30 subjects were enrolled into each arm with baseline viral loads > 10,000 copies/mL. The treatment experienced patients had the nucleosides analogs stopped at the beginning of therapy, so all patients were treated with only two drugs. The rationale for this study rests, in part, on the observation that efavirenz increases the concentration of nelfinavir. Efavirenz reduces the concentrations of indinavir and saquinavir, and the doses of these drugs should be increased if combined with efavirenz.
After 16 weeks of treatment, approximately 80% of naive patients and 65% of experienced patients had viral loads < 400 copies/mL. This difference was not statistically significant. Moderate to severe adverse experiences included diarrhea in 16% of patients, rash in 17%, and CNS toxicities in 11%.
This study confirms the antiviral activity of efavirenz when used in combination with a protease inhibitor as part of dual therapy. The study only reported on patients treated for 16 weeks of therapy, and a greater proportion of subjects may experience viral load reductions below quantifiable levels as the study progresses. However, the fact that resistance to efavirenz results in cross resistance to all of the NNRTIs (as is true for all of the currently available drugs in this class) suggests that the ideal strategy for use of this drug is as part of triple combination therapy.