Rob Murphy presented preliminary 48-week data from the Atlantic Study as about 80% (n=235) of the 298 enrollees have completed 48 weeks and 61% (181) have 48-week viral load data available. This study compares IDV and NVP to a triple NRTI regimen and continues for 144 weeks in total. A lipodystrophy analysis is being conducted.

Nevirapine was administered 400 mg once daily after the dose lead-in of 200 mg. 3TC was taken 150 mg BID; indinavir was taken 800 mg TID. DDI was dosed once daily:

The baseline viral load is low and limits the interpretation of the data. The overall median baseline viral load of 4.36 (23,000 copies/ml) was a little bit higher here as more data is available than the 16,000 copies/ml that was reported at the Retrovirus Conference in February ’99. The median baseline viral loads for each treatment group were about the same. The baseline CD4s are about 447.

Only about 12% (28 of 235) overall had >100,000 copies/ml at baseline: 9 (11.4%) in the IDV group, 6 (8.5%) in the NVP group and 11 (12.9%) in the 3TC group.

CD4s increased about 150 in each arm by 48 weeks.

After 48 weeks of follow-up using the ITT analysis. Murphy said that although there is no statistical significance between the arms in this table there is a suggestion of differences in the <50 analysis. There are about 55 persons in each arm:

As-Treated Analysis (n=181). Again, although there is no statistical significance to the differences between treatment arms there is a trend for the 3TC arm to underperform in the <50 analysis:

3TC Arm May Underperform in <50 Analysis When Viral Load is >51,000 copies/ml. The investigators did a post hoc analysis of viral load response for those above and below 51,000 copies/ml at baseline. Murphy said to remember that this still is a preliminary analysis and not all the data has been analyzed yet. There were no statitistically significant differences between the IDV and NVP arms whether by <500 or <50 copies/ml. But there was a trend approaching statistical significance (p-0.08) that the 3TC arm underperformed in the <50 group for individuals with >51,000 copies/ml at baseline (55% vs 31.6%). The reason this trend loses statistical significance could be because the number of people in this group was small.

Grade 3 & 4 Clinical Toxicities (related to study meds), Grade 3 & 4 Lab Abnormalities, and Study Discontinuations. There was a total of 57 (24%) study disconyinuations: 20 in the IDV arm, 12 in the NVP arm and 25 in the 3TC arm. Discontinuations due to adverse events were 12 in the 3TC arm, 7 in IDV, and 5 NVP.

There were 6 cases (grades 3 & 4) reported for GI-related events in the IDV (n-79) and 3TC (n-85) arms (nausea, vomiting, diarrhea; and 0 in the NVP arm). There were 5 cases of grade 3 & 4 rashes reported in the NVP arm (n-71) and none in other arms. Four cases of kidney stones reported in the IDV arm (n-79). There were 3 cases reported for neurological toxicities in the NVP arm, 3 in the 3TC arm, and none in the IDV arm.

There were 4 cases of grade 3 & 4 elevated LFTs in the IDV arm, 9 in NVP arm, and 5 in 3TC arm. There were 7 cases of elevated y-GT in the NVP arm and one each in other arms. Elevated bilirubin—14 in IDV arm; elevated amylase—3, 3, and 6 in IDV, NVP and 3TC arms, respectively.

1. Study # 006, 72 wks EFV+AZT+3TC; data at 72 weeks is same as was for 48 & 60 wks. The enrollment goal is 1200 people--about 450 per arm.

Mean baseline viral load 58,900 copies/ml; CD4s 332; 83% treatment-naive; all were NNRTI and 3TC naive.

*Observed data analysis: <400 copies/ml--98% (n=99);

*ITT (Intent-To-Treat) is the more stringent analysis in which non-completers=failures: 67% <400 copies/ml (n=145)

*Ultrasensitive analysis - <50 copies/ml--89% Observed data; 60% ITT

*The study investigators presented a new analysis for individuals called "Duration of Response: all failures as endpoint": after about 700 days about 83% (n=35) of participants remained suppressed. When looking at virological failures only (viral load) about 90% (n=36) remained suppressed. When looking at individuals with baseline >100,000 copies/ml (mean- 281,000 copies/ml, n=133 and mean CD4s of 126, about 85% (n=23) remained suppressed. Looking at virological failures only in this >100,000 copies/ml group about 90% remained suppressed

* CD4s increased about 225 from baseline to week 72

* About 47% experienced new nervous system symptoms within the first 28 days. Symptoms appear to resolve for most people within the first few weeks. The study reported about 5% discontinued with the first month due to nervous system side effects. Study conditions may underestimate real-life situations

* Discontinuations: 24% (105/422) in the EFV+AZT/3TC arm, 35% in the EFV+IDV arm and 41% in IDV+AZT/3TC arm

2. EFV+d4T/ddI -

*baseline RNA 71,000 copies/ml; CD4s 289, n=61

*24 weeks; <400 copies/ml, observed data- 90% (n=48), ITT- 75% (n-57);

<50 copies/ml-- 81% observed data, 68% ITT;

>100,000 copies/ml, 67% <50 ITT (n=24)

*42% experienced Nervous system symptoms 18/22 mild

onset median 1 day, median duration 15 days

*rash- 19% (n=10) 8/10 mild

onset median 10 days; duration median 6.5 days; 1 discontinuation due to rash

* This regimen did not perform quite as well as EFV+d4T/3TC or with AZT/3TC. DuPont researchers suggested it may have to do with difficulty in taking ddI. DDI was taken once daily in this regimen

3. EFV+d4T/3TC

*baseline--n=68; 45% African-American enrollment; CD4s 380, 75,000 copies/ml viral load

* wk 24- n=33; <400 copies/ml-- 100% observed data, 92% ITT; <50 copies/ml-- 97% observed data, 89% ITT; >100,000 copies/ml-- 92% <50 ITT (n=12), 100% <400 copies/ml

Although the d4T/3TC is considerably smaller than 006 (AZT/3TC) the results suggest that EFV/d4T/3TC may be more effective regimen possibly because d4T is easier to tolerate.

This study compared abacavir + AZT/3TC to indinavir + AZT/3TC. Subjects were stratified by baseline viral load by >100,000 copies/ml or 10,000 to 100,000 copies/ml. After 16 weeks individuals were permitted to swtich to open-label if viral load was >400 copies/ml on 2 consecutive occasions.

The study design may have affected compliance and some of the data outcome. All patients received 16 tablets per day (TID) to blind the participants from identifying which regimen they were on. In addition all were required to observe IDV eating and hydration requirements. This may have affected the data outcome. However, the number of pills containing active drug was 4 in the triple NRTI arm (12 were placebo) and 12 in the indinavir arm (2 placebo). In real-life abacavir is a BID regimen and not affected by food intake.

At baseline the median viral load and CD4 was 70,795 copies/ml and 359 in the abacavir arm (n=282); 180 (64%) had between 10,000-100,000 copies/ml and 102 (36%) had >100,000 copies/ml. In the IDV arm the baseline parameters were about the same: baseline median viral load was 66,000 copies/ml, CD4s 360, 63% 10,000-100,000 copies/ml, 37% >100,000.

At week 48 the discontinuation rates were high at 38% in the abacavir arm and 41% in the IDV arm--17% (n=44) for adverse events in the avacavir arm, 21% (n=55) in the IDV arm for adverse events. Common adverse events leading to discontinuation-- nausea, fever, nausea & vomiting, malaise & fatigue, skin rashes, headaches. These include the symptoms of abacavir hypersensitivity. Study investigators report 19 potential (7.3%) abacavir related hypersensitivity cases: 11/19 were judged serious; 8 hospitalized; 1 person died after rechallengeOnly 5% in each group reported discontinuing due to virologic failure.

*As treated analysis-- <400 copies/ml at week 48: 94% in abacavir arm and 86% in IDV arm

* Intent-To-Treat-- <400 copies/ml: 51% in each arm. All discontinuations are considered failures in this analysis

* When comparing the 2 viral load stratifications (using ITT analysis) there appeared to be no difference between the IDV and ABC arms in terms of reducing VL <400 copies/ml. For both groups about 60% had <400 copies/ml

*Ultrasensitive ITT analysis (<50 copies/ml) in the 10,000 to 100,000 group--about46% had <50 copies in both treatment groups

* But, using the ultrasensitive test and an ITT analysis in the >100,000 copies/ml group there was a difference--45% < 50 copies/ml in the IDV group and 31% had <50 in the abacavir group

* However, in these subjects with high baseline HIV RNA, no differences were observed in the time to viral load rebound (to greater than 400, 1000, or 5000 copies/mL).

* CD4 increases were about 142 for each group