Preliminary data from two studies exploring nelfinavir twice daily (bid) dosing (24 weeks and 32 weeks) are reported below. Preliminary 32 week data for indinavir bid (twice daily dosing) is also reviewed.

In brief, investigators reported that in one nelfinavir study, 78% of those on a bid regimen who had <400 copies/ml also had <50 copies/ml at week 32. The pharmacokinetics data for nelfinavir bid, which is shown below, is encouraging. In the Merck indinavir bid regimen study, at week 32, 60% of participants using a bid regimen had HIV RNA <50 copies/ml, and 70% were <500 copies/ml (n=18). The data from these studies are promising and there is hope that a bid indinavir regimen will be equally effective as the standard tid regimen (every 8 hrs). However, long term data of a year or more on a larger number of individuals would be helpful in confirming the 32-week data.

Data is mounting that demonstrates that a viral load reduction to <50 copies/ml increases the durability of the antiviral response over reaching just <400 copies/ml. Therefore, some researchers have said the goal of therapy should be <50 copies/ml. Based on that, the percentage below 50 copies/ml in these studies may be an important measure of the bid regimens.

Dr. M. Sension and co-authors reported a preliminary 24-week analysis of an open label pilot study of 46 treatment naive individuals with mean baseline CD4 and viral load of 342 cells and 137,428 copies/ml. The purpose of the study is to assess the safety, tolerability, and antiviral activity of a BID regimen of nelfinavir. Of the 46 participants, 36 received 1250 mg BID nelfinavir + d4T/3TC or AZT/3TC, while10 patients received 1000 mg nelfinavir + AZT/3TC. There were three treatment groups.

Group 604 took 1250 mg bid NLF + d4T/3TC; Group 603 took 1250 mg bid NLF + AZT/3TC; Group 606 took 1000 mg bid NLF + AZT/3TC. See Table 6

Discontinuations: There were a total of 10 discontinuations. Seven discontinuations were reported in the 604 group: non-compliance (3), lost to follow-up (3), and adverse event (1). Three discontinuations were reported in the 603 group: non-compliance (2) and lost to follow-up (1). No discontinuations were reported in the 606 group.

Week 24 Changes in CD4 and Viral Load from Baseline. There were 22, 14 and 10 patients in groups 604, 603 and 606 respectively, at baseline. At week 24, the two 1250 mg bid arms (n=11 in d4T/3TC arm, 4 in AZT/3TC arm) displayed a mean reduction in HIV RNA of about 2 log. The 1000mg bid group displayed a reduction of about 2.2 log from baseline. The CD4 increases were 100+ at week 24 for the two 1250mg bid groups and about 50 for the 1000mg bid NFV group. See Table 7

Adverse Events. The only major side effect reported was diarrhea with an overall incidence rate of 30%. Diarrhea effected 8/22 in the NFV 1250 arm taking d4T+3TC, 2/14 in the 1250 arm taking AZT/3TC and 4/10 in the NFV 1000mg arm. Over the counter anti-diarrheal medications as well as diet is reported to help reduce or eliminate the side effect. Eliminating fried food, eating binding foods such as bananas & matzoh, and eating yogurt has been helpful to individuals in preventing eliminating or reducing diarrhea. Detailed side effect data is available on the web site.

A second larger study is exploring nelfinavir bid in combination with d4T+3TC. A. Peterson and others reported 32-week preliminary findings from an interim look at results from a study in Europe. Initially, patients were randomized in a double blinded fashion to one of 3 bid nelfinavir regimens (750 mg, 1000 mg, or 1250 mg) or to the standard tid regimen of 750 mg 3X/day. Everyone also received d4T+3TC. During the course of the study it was changed to an open study of 1250 mg bid nelfinavir vs 750 mg tid nelfinavir. The other two bid regimens were eliminated when it was realized that they were probably suboptimal. All individuals receiving those two regimens were switched to the 1250mg-bid regimen. Because the arms were still blinded at this time, the data from all three bid arms were reported combined or this analysis. See Table 8

32 Week Viral Load and CD4 Changes. Patients started this study on either a bid or tid regimen. The tid regimen was given to 75 patients, while 203 people were on the bid regimens. After 32 weeks, the mean reduction in HIV RNA from baseline was -2.2 log for the bid regimen (n=84) and -2.4 log for the tid regimen (n=31). In both the tid and bid groups, 80% of patients achieved HIV RNA below the level of detection (<400 copies/ml, Roche Amplicor Test). Of those who achieved <400 copies/ml, 78% (bid) and 53% (tid) of patients were <50 copies/ml using the Roche Ultrasensitive PCR test. The CD4 increase from baseline was 181 for those taking the bid regimen and 155 for the tid regimen.

Discontinuations. In the preliminary findings, authors reported only one treatment failure in the bid regimen and one in the tid regimen. Overall, there have been two discontinuations in the tid regimen, one by patient request. There have been eight discontinuations in the BID regimen, a few for adverse events, one for intercurrent illness, one for patient request and one for non-compliance.

Pharmacokinetics (PK). The 24 AUC (area under the curve) is about 15% higher for the bid regimen than the tid regimen. The Cmax is also higher (50%) while the authors stated that the trough was similar for both tid and bid regimens (0.9 vs 0.7 mg/L, respectively). The authors concluded that the PK profiles are comparable for both the tid and bid dosing regimens. See web site for individual data.

Treatment Related Adverse Events of Moderate or Severe Intensity in ³2% of Patients. Eight cases (12.3%) of diarrhea were reported in the tid regimen arm while 23 cases, or 13.1%, of diarrhea were reported in the bid regimens. Three cases of nausea (4.6%) were reported in the tid arm and 4 cases (2.3%) in the bid regimens.

Bach-Yen Nguyen, MD of Merck Labs, reported preliminary 32 week data on a indinavir bid regimen. The study compares two bid regimens with the standard tid regimen of indinavir every 8 hours. The regimen consisted of 800 mg indinavir every 8 hrs (n=29), 1000 mg indinavir every 12 hours (n=28) and 1200 mg every12 hours (n=30). In addition, all participants received AZT and 3TC. Study participants were protease inhibitor and 3TC naive. Almost half, 49%, of the study participants were Caucasian, 23% were black, 25% Hispanic. The participants were 80% men and 20% women. A larger study is underway to confirm these study results. Merck is also conducting a study to assess switching individuals who are currently taking the tid regimen to the bid regimen. The median baseline CD4 and viral load were about equal for all three arms: 266-294 CD4 and 47,800 to 52,480 copies/ml. See Table 9 and 10.

Some clinicians and researchers have suggested that periodically measuring the level of indinavir blood (AUC, Cmin) might be useful in assuring that a person was achieving adequate blood levels. Drug failure can result from inadequate drug blood levels. On the other hand, Merck believes that for indinavir, dosing decisions should not be based on measuring indinavir PK levels because there is too much intrasubject variability of blood levels. They believe a person can have one blood level today, a two-fold difference another day and then go back to the previous level which is not predictive of sustained antiviral effectiveness.

Table 7. Nelfinavir BID Percent Below Detection