HIV AIDS News [International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

[22340] A double-blind, placebo-controlled study to assess the safety, tolerability and
antiretroviral activity of efavirenz (EFV, SUSTIVA TM, DMP 266) in combination with
open-label zidovudine (ZDV) and lamivudine (3TC) in HIV-1 infected patients [DMP
004]
12th World AIDS Conference
June 28 - July 3, 1998
Geneva, Switzerland
D. Mayers, J. Jemsek, E. Eyster, K. Tashima, M. Thompson, N. Ruiz
The Efavirenz Clinical Development Team; DuPont Merck, Pharmaceutical Company,
Wilmington, DE; National Naval Medical Center, Bethesda, MD; Nalle Clinic, Charlotte, NC;
Hershey Medical Center, Hershey, PA; Family Health Center at Starr, Falls River, MA; AIDS
Research Consortium of Atlanta, Atlanta, GA. USA
Background: EFV is an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI).
Pharmacokinetic evaluation supports once-daily administration. Objectives: 1) To evaluate the
safety, tolerability and effectiveness (antiretroviral activity) of EFV in combination with
ZDV+3TC in nucleoside analogue experienced asymptomatic or mildly symptomatic HIV-1
infected patients, and 2) To assess the pharmacokinetics of multiple doses of EFV in this patient
population and to determine if there is a pharmacokinetic interaction between ZDV+3TC +EFV.
Methods: Multicenter, randomized, 16 week double-blind study of EFV, 400 or 600 mg qd, in
combination with open-label ZDV (600 mg/day) plus 3TC (150 mg bid). Inclusion Criteria:
ZDV+3TC treatment for at least 8 weeks prior to beginning treatment, plasma HIV-1 RNA
>2500 copies/mL measured 21 days prior to beginning of treatment, CD4 >50 cells/mm3.
Exclusion Criteria: Prior treatment with any NNRTI or with any protease inhibitors. Study
Design: Cohort I (N=15) 400 mg EFV qd, or matching placebo, was added to ongoing
combination ZDV+3TC therapy; Cohort II (N=15) EFV 600 mg qd, or matching control, was
added to ongoing ZDV+3TC therapy; Cohort III (N=63) EFV 400 mg qd or 600 mg qd was
added to combination ZDV+3TC therapy. Patient Characteristics at Entry, Cohort III: Male=76
%, Caucasian=59%, mean age =37.7 years (~7.5 years), median months prior antiretroviral
therapy=9.9, mean years HIV-1(+)=5.6 (~3.4), mean copies/mL HIV-1 log0 RNA= 4.04 (~0.55),
CD4=357.4(~ 167.8) cells/mm3. There were no statistically significant differences between
treatment groups in characteristics at entry. Results, Cohort III: Antiretroviral Activity
(copies/mL). (After week 16 of therapy) mean decreases in HIV-1 RNA (Truncated values, <400
assigned a value of 400): ZDV+3TC+EFV(400 mg) = -0.65 (~0.75), ZDV+3TC+EFV 600 mg=0.49(~0.15); ZDV+3TC+placebo= -0.05 (~0.11) (p<0.05, placebo vs 400 mg); (p<0.05, placebo vs
600 mg). Less than 50% of patients in the EFV 400 mg qd or placebo arms achieved <400
copies/mL. While 72% of patients in the EFV 600 mg qd arm achieved <400 copies/mL, the
median time to failure was 10 weeks (p=0.05). Increase in CD4 (cells/mm3): ZDV+3TC+ EFV 400
mg=+50.34(~14.37), ZDV+3TC+EFV 600 mg=+43.19(~24.80) (p>0.05, 400 mg vs 600 mg),
ZDV+3TC+EFV placebo= -9.48(~17.35) (p<0.05, placebo vs 400 mg), (p>0.05, placebo vs 600 mg).
Tolerability. After 16 weeks of therapy, some patients in all treatment groups described
potentially drug-related adverse events, most of which were mild to moderate in intensity.
Overall, EFV did not alter the general tolerability or safety of the combination of ZDV+3TC.
Conclusions: Due to transient antiretroviral activity with a median time to failure of 10 weeks,
the addition of EFV 600 mg po qd as functional monotherapy to the regimen of patients with
active viral replication is not recommended.