D4T+DDI+Nevirapine: 24 weeks

F Raffi, of France (abstract 88-I) reported preliminary24 and 36 week data from the 52 week Virgo Trial, which is evaluating tolerance,virologic and immunologic effect of D4T+DDI+nevirapine in an open-labelnon-comparative study. Secondary study objectives are to look at aspectsand dynamics of immune reconstitution, relation of adherence to failureand incidence of RT mutations and relation to failure. After the initial60 patients were enrolled in this open-label study, 40 more were added takingthe regimen of bid d4T+once-a-day ddI and nevirapine. Today's data focuseson the first 60 patients.

Regimen-- d4T twice daily 30 mg <60 kg, 40 mg >60kg

ddI once-a-day 300 mg <60 kg, 400 mg >60 kg

nevirapine 200 mg once-a-day for 14 days, then 200 mg bid

This is a relatively low pill burden regimen.

Investigators are assessing compliance, tolerance, CD4,HIV-RNA (500 copies detection limit), 50 copies detection limit, CD4/45RA+,CD4/45RO+ (naïve & memory CD4 cells), and genotyping.

• Baseline median CD4 count - 415 (range- 215-501), mean 427
• Baseline plasma HIV-RNA - There is confusion regarding what the baseline viral load is. The slide in the oral presentation by Raffi said baseline median viral load was 4.5 log which is about 31,000 copies/ml. However, in the ICAAC abstract book the mean baseline viral load is reported as 108,000 copies/ml and also as 4.6 log. 4.6 log is 40,000 copies/ml. When I spoke with Raffi personally, he said the baseline viral load was about 100,000 copies/ml. This is important because you want to know if this combination is effective for individuals with higher baseline viral load.

10 patients discontinued due to side effects before week24, 1 patient lost to accidental death, 1 patient lost to follow-up.

Cutaneous Rash- 14/60 (23%)

• Grade1 = 6
• Grade 2 = 5 (dose reduction ­1, disct ­ 2)
• Grade 3 = 2 (disct=2)

Rashes occurred between day 8 and day 28 (mean=15.1 days)

Associated with LFT elevations=4/14

Protocol Defined Toxicities (grade 2-4)

Cutaneous rash n=8

• 4/8 disct; incidence of disct at month 1= 6.7%

LFT elevations n=9

• 2/9 disct (all 3 drugs)

Digestive symptoms n=3

Peripheral neuropathy n=3

• 1 disct all 3 drugs @week 24
• d4T disct=2 (week 28, week 36), switched to AZT

Miscellaneous n=4

CD4 and plasma Viral Load Change From Baseline

Week	CD4	Mean HIV-RNA	% <500 copies/ml
24 (n=52)	+162	-2.10 log	88% (46/52)
36 (n=20)	+193	-2.13 log	80%

At week 24, of the 46 patients <500 copies/ml, 41 weregiven the ultrasensitive viral load test and 30/41 had <50 copies/ml(73%).

Although Raffi did not delineate between on-treatment andintent-to-treat analaysis, my calculation of intent-to-treat in this studyis-- 46/60 had <500 copies/ml (76.6%); 30/60 had <50 copies/ml (50%)at week 24. They did not stratify by viral load <100,000> copies/ml,but Raffi commented in response to question from audience without showingdata that there were individuals in study with >200,000 copies/ml withsame effect. I would reserve judgement on that until data is available.He reported a 10% disct rate due to adverse events at week 24.

Raffi showed preliminary data on the once-a-day DDI andnevirapine with d4T bid. At week 4 (n=28)-CD4 increased 95 cells, HIV-RNAreduced by 1.94 log, 63% <500 copies/ml.