Efavirenz + AZT/3TC: 36 week Update

Week 24 data of this study was reported at Geneva and week 36 data was reported at ICAAC. As well, several additional studies of efavirenz were reported at ICAAC. They included EFV+indinavir, EFV+nelfinavir, and a late-breaker of efavirenz+nelfinavir in children. This report will present the 36 week EFV/AZT/3TC data and the other studies will be reviewed in following reports.

It was reported that EFV --

• has a long halflife of 40-55 hours which permits once-a-day dosing
• may be taken with or without food; high fat meals should be avoided because EFV blood levels can increase thereby potentially increasing side effects

This study (protocool #006) compared EFV+AZT/3TC to EFV+indinavir and Indinavir+AZT/3TC. Participants were required to be PI, NNRTI and 3TC naive, and have >10,000 copies/ml and >50 CD4. 85% were treatment naive; 60% were caucasian, 17% black, and 19% hispanic; 86% were male. There was no statistical differences in demographics between the 3 treatment arms. The mean baseline CD4 and viral load were about the same for each arm--overall mean-345 CD4, 58,884 copies/ml.

Due to new FDA review procedures studies are now being statistically analyzed by 3 different methods. This is confusing but I'll try to define each clearly. Making it more difficult is that sometimes a company will define their as-observed or intent-to-treat analysis differently than another company. In each instance I will try to explain their definitions.

• The on-treatment analysis does not include individuals who have discontinued or dropped out of the study for any reason. The data is based on data available at the timepoint. No data is imputed. Since this data includes only people who've remained on therapy the percent undetectable will be higher than the percentages for the other two methods. It cam be helpful to look at the data from all 3 analysis. It is difficult to report, however, all 3 analysis' for every drug. But, I will label which analysis you are seeing.
• The Intent-To-Treat (ITT) Last Observation Carried Forward (LOCF) analysis uses the last available value and carries it forward to the current time point. So, if a person had undetectable viral load at week 16 but there was no viral load data at week 24 the week 16 data would be used at week 24
• The Intent-To-Treat Noncompleter=Failure (NC=F) is the most stringent of the 3 methods. All participants are included even if individuals dropped out, moved, died for unrelated reasons, or failed the therapies. All drop outs and missing data are considered treatment failures.

Viral Load Results at Week 36 only for the EFV+AZT/3TC Treatment Arm

• on-treatment analysis: 95% <400 copies/ml (n=106)
• LOCF: 85% <400 copies/ml (n=154)
• Intent-To-Treat (NC=F): 73% <400 copies/ml (n=140)
• on-treatment, baseline viral load >100,000 copies/ml: 95% <400 copies/ml
• LOCF, baseline viral load >100,000 copies/ml: 85% <400 copies/ml

Ultrasensitive Viral Load Data at Week 36 for EFV+AZT/3TC arm only

• On-treatment: 88% <50 copies/ml (n=105)
• LOCF: 66% <50 copies/ml (n=154)
• NC=F: 64% <50 copies/ml (n=144)

At week 24, 76% were reported to have <50 copies/ml using the on-treatment analysis. The difference between 88% and 76% may not be statistically significant.

The mean CD4 increase was about 180 at week 36.

Premature Terminations at 36 Weeks

Reason	EFV+AZT+3TC	EFV+IDV	IDV+AZT+3TC
TOTAL	25%	30%	41%
Adverse Experiences	6%	5%	19%
Death	0	<1%	0%
Protocol Violation	3%	7%	6%
Withdrew Consent	10%	11%	11%
Lack of Effect/Tx Failure	1%	1%	<1%
Randomized, but not dosed	4%	5%	4%
other	0	<1%	0%

AEs Leading to Discontinuation

EFV+AZT+3TC	(10/154)	EFV+IDV	(9/148)	IDV+AZT+3TC	(28/148)
nervous system	3	nervous system	3	gastrointestinal	15
gastrointestinal	2	rash	3	nephrolithiasis	4
Rash	1	AST & ALT	1	anemia	3
other	4	other	2	other	6

Summary of New-Onset of Rashes

	EFV+AZT+3TC	EFV+IDV	IDV+AZT+3TC
TOTAL	29%	34%	16%
Maximum Severity
grades 1 & 2	29%	32%	16%
grade 3	0%	2%	0%
grade 4	0%	0%	0%
% requiring disct of EFV for rash	1%	2%	-

Summary of Nervous System Symptoms

	EFV+AZT+3TC	EFV+IDV	IDV+AZT+3TC
TOTAL	55%	49%	24%
Maximum Severity
Mild/Moderate	51%	48%	24%
Severe	4%	1%	0
Maximal	0	0	0
% discontinuing EFV	2%	1%	-