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Trizivir-Efavirenz Induction-Maintenance Study
Reported by Jules Levin
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Martin Markowitz (Clinical Director, Aaron Diamond AIDS Research Center, NYC) reported in an oral presentation on an induction-maintenance study at the IAS Conference: "Induction of Antiretroviral-naive HIV-infected Subjects with Trizivir and Sustiva for 48 Weeks (ESS40013)". The preliminary 48 week results find this induction 4-drug regimen to be potent. There was a high rate of study discontinuation by patients due to drug-related adverse events, but there were few viral failures.
This study was designed to test a 4-drug induction 3-drug maintenance approach to ART. Markowitz said he was pleased he could guide design of this study because he thinks 48 weeks of induction are key to reducing virus to very low levels and to the long term effectiveness of this approach. Highly active quad regimens provide potent and durable suppression of viral replication. They achieve optimal responses in a broad range of patients including patients with high HIV-RNA (viral load) and low CD4. However, compared to triple regimens, quad regimens are more costly, may be more toxic, a more complex regimen, and have increased adherence demands. The induction maintenance approach is to use quad therapy to quickly reduce viral burden and triple therapy for long-term viral suppression. This approach may be particularly effective for high viral load.
This is a phase IV, 96-week, randomized, multicenter study. Co-sponsored by GlaxoSmithKline. 448 ART-naive patients with above 25,000 copies/ml viral load and no CD4 criteria receive Trizivir plus efavirenz for 48 weeks. After 48 weeks patients with <50 copies/ml viral load (n=282) are randomized to Trizivir plus efavirenz or Trizivir for 48 weeks. Markowitz said that at randomization residual viral burden is minimal. Significant time with vRNA <50 c/ml is important. Non-adherent subjects likely are not eligible for randomization.
The objectives of the 48-week induction phase is to assess efficacy, safety, and tolerability of Trizivir+efavirenz, and to analyze virologic failure. The objectives of the 48-96 week maintenance phase is to assess the durability, safety, and tolerability of Trizivir+efavirenz vs Trizivir; to analyze self-reported adherence; quality of life; fasting lipid parameters, and analyze virologic failure.
BASELINE PATIENT CHARACTERISTICS (n=448). Median age 38 yrs; 84% male; 49% White, 38% Black, 11% Hispanic; 14% CDC Class C; median viral load 120,000 copies/ml (range 48 to 7,240,000 copies/ml); 56% of patients have >100,000 copies/ml; median CD$ count 210 (range 2-4197); 48% have <200 CD4s; 21% have <50 CD4s.
SUBJECT DISPOSITION
--37% of patients discontinued from study regimen by week 48
Primary reason for premature discontinuation:
--adverse event 12%
--consent withdrawn 8%
--lost to follow-up 6%
--protocol defined viral failure 5%
--investigator defined viral failure 1%
--protocol violation 1%
--clinical progression <1%)
--poor CD4 response (investigator) <1%
--other 4%
TREATMENT RELATED ADVERSE EVENTS grades 2-4 with 5% incidence
--1 or more drug related Grade 2-4 AE- 46%
--nausea - 11%
--suspected hypersenstivity to abacavir- 7%
--rashes- 6%
--fatigue- 6%
--sleep disorders- 6%
--vivid dreams- 5%
VIRAL RESPONSE <50 copies/ml, week 48
--61% of patients had <50 copies/ml (ITT M=F)
--90% had <50 copies/ml (ITT observed)
RESPONSE BY BASELINE VIRAL LOAD VALUE
Markowitz displayed a graph examining viral response by baseline viral load (ITT observed)
--Patients with <100,000 copies/ml (n=130) at baseline appeared to have the best response, 95%.
--Patients with 100,000 to 249,999 c/ml (n=153), 85%
--Patients with 250,000 to 499,999 c/ml (n=55), 89%
--Patients with 500,000 to 749,999 c/ml (n=18), 78%
--Patients with >750,000 c/ml (n=20), 90%
In a curve displaying time to viral response <50 c/ml, patients with <100,000 c/ml at baseline responded more quickly in terms of viral load decline. Patients with 100,000 to 750,000 didn't respond as quickly. But on average by week 16 both of these groups had similar proportions of patients <50 c/ml. However, the group with >750,000 c/ml had a higher proportion of patients >50 c/ml at week 16. At week 52 the two groups (<100,000 and 100,000-750,000) had similar proportions of patients below 50, and the >750,000 group had less patients below 50 copies/ml. By week 40 there were not many patients in the analysis. But throughout the period after week 4 there was a wide gap in proportion <50 c/ml between the <100,000/100,000-750,000 and the >750,000 groups.
VIRAL RESPONSE <50 COPIES/ML AT WEEK 48 BY BASELINE CD4 COUNT
(ITT observed)
--patients with >350 CD4s, 97%*
--CD4 200-349, 90%
--CD4 50-199, 89%
--CD4 <50, 84%*
*(p=0.012)
GENOTYPIC PATTERNS at VIROLOGIC FAILURE on TZV+EFV (n=22)
--5 patients (23%) had wild-type or as baseline
--2 (14%) had M184V alone
--5 (23%) had EFV resistance alone
--6 (32%) had M184V+EFV resistance
--2 (9%) had M184V+EFV +TAMs resistance
--1 (5%) had K65R+EFV resistance
--1 (5%) had K65R+M184V+EFV resistance
EFV resistance=K103N, Y181C, Y188L, G190S, or P225H
EFV resistance- 14 (64%)
M184V- 11 (50%)
K65R- 2 (9%)
TAMS- 2 (9%)
Median VL at viral failure=20,000 c/ml
Markowitz summarized:
--Trizivir plus EFV is a potent regimen in ART-naive subjects
--virologic suppression and immunologic response was sustained through 48 weeks
--quad regimen of TZV+EFV had a high rate of study discontinuations
--protocol defined viral failure was rare (5%)
--majority of subjects who failed are:
resistant to NNRTIs
susceptible to all NRTIs except 3TC
susceptible to protease inhibitors
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