Reported by Jules Levin, Executive Director of NATAP (1 April 1998)

Following is the data from studies exploring twice daily regimens for taking nelfinavir and indinavir. There are two bid NFV studies reviewed below. One is small and 24 weeks are reported for it. The other is larger and 2 weeks of preliminary are reported - the study was inteded for 96 weeks. The patients in that study will continue to be followed. Investigators reported that at week 32, 78% of those on a bid regimen who were <400 copies/ml were also <50 copies/ml. The data from these bid studies are encouraging. Data appears to be mounting that reaching <50 copies/ml increases the durability of the antiretroviral response over reachinb just <400 copies/ml. Based on that, the % below 50 copies/ml may be an important measure of a regimen. The PK data for NFV bid,  which is shown below, is also encouraging. However, longer term data would be helpful in confirming this 32 week data.

In the Merck 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). Although the data seems encouraging that a BID indinavir regimen will be equally effective as the standard TID regimen, longer term data of a yeaer of more on a larger number of individuals would be helpful in confiming the 32 week data.

Some researchers have said that pharmacokinetic parameters (AUC, Cmin, Cmax) should correlate with viral load response. Merck says pharmacokinetics (PK) were not studied in this trial because the relationship between PK and antiviral response for is not known. Company officials maintain that you should rely on the clinical data. Merck says that viral load resonse to indinavir is not necessarily correlated with trough concentrations, but that daily AUC may be important to viral load response. Although they did not conduct a PK study for this trail they say that they expect daily AUC would be the same or a little higher for the bid as the tid regimen. They maintain that 60% <50 copies/ml is the important clinical data here that should be used to judge the regimen. Merck will be conducting a PK study in a larger trail planned to test the bid dosing.

Nelfinavir 1250 mg BID

The preliminary results of two studies of nelfinavir twice a day dosing were reported at the 5th Human Retrovirus Conference in Chicago in early February 1998. 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.

36 participants received 1250 mg BID nelfinavir + d4T/3TC or AZT/3TC. 10 patients received 1000 mg nelfinavir + AZT/3TC. AZT was administered as 300 mg bid; d4T was taken as 30 or 40 mg bid depending on the weight of patient; and 3TC was taken 150 mg bid.

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.

Ethnicity

18/46 (39%) participants were Caucasian; 6 (13%) Black; 16 (34%) Hispanic; 3 (6%) Asian and 1 Pacific Islander.

Discontinuations

There were a total of 10 discontinuations. 7 discontinuations were reported in the 604 group: non-compliance (3), lost to follow-up (3), and adverse event (1). 3 discontinuations were reported in the 603 group: non-compliance (2) and lost to follow-up (1). No discontinuations were reported in the 606 group.

Results

Week 24 Changes in CD4 and Viral Load from Baseline

There were 22, 14 and 10 patients in groups 604, 603 and 606 at baseline. At week 24, the two 1250 mg bid arms (n=11 in d4T/3TC arm, n=4 in AZT/3TC arm) displayed a mean reduction in HIV RNA of about 2 log. The 1000 mg bid group displayed a reduction of about 2.2 log from baseline.

The CD4 increases were 100+ at week 24 for the two 1250 mg bid groups and about 50 for the 1000 mg bid NFV group.

*PCR test was used. Ultrasensitive PCR was used for <50 copies. Of the 11 patients in this arm 8 were tested by Ultrasensitive test.

Adverse Events greater than or equal to Grade 2

A second larger study is exploring nelfinavir bid in combination with d4T+3TC. A Peterson and others reported findings from an interim look at results (abstract #373) 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 1250 mg bid regimen.

Because the arms were still blinded at this time the data from all three bid arms were reported combined or this analysis.

Results

75 patients started the study on the tid regimen, and 203 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); 80% of patients in both groups, TID and BID, 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 ultrasenstive PCR test; the CD4 increase from baseline was 181 for those taking the BID regimen and 155 for the TID regimen.

Discontinuations

The authors reported only I treatment failure in the BID regimen and 1 in the TID regimen, so far in these preliminary findings. Overall there have been 2 discontinuations in the TID regimen -- 1 by patient request; and there have been 8 discontinuations in the BID regimen -- for adverse events, I for intercurrent illness, 1 for patient request and 1 for non-compliance.

Pharmacokinetics

The 24 AUC (area under the curve) is about 15% higher for the bid regimen than the tid regimen. The Cmax is also higher while the authors stated that the trough was similar for both tid and bid regimens. The authors concluded that the PK profiles are comparable for both the tid and bid dosing regimens.

Treatment Related Adverse Events of Moderate or Severe Intensity in ³ 2% of Patients

8 cases (12.3%) of diarrhea were reported in the TID regimen arm; 23 cases or 13.1% of diarrhea were reported in the BID regimens. 3 cases of nausea (4.6%) were reported in the TID arm and 4 cases (2.3%) in the BID regimens.

Indinavir: Week 32 Data of Every 12 Hours Regimen vs. Every 8 Hours

Bach-Yen Nguyen, MD of Merck Labs reported preliminary 32 week data on a indinavir BID regimen. The study compares 2 BID regimens with the standard TID regimen of indinavir every 8 hours: 800 mg indinavir every 8 hrs, 1000 mg indinavir every 12 hours and 1200 mg every 12 hours. In addition all participants also received AZT 300 mg every 12 hours and 3TC 150 mg every 12 hours. Study participants were protease inhibitor and 3TC naive. 49% of the study participants were Caucasian, 23% black, 25% Hispanic, 80% male and 20% female.

A larger study is underway to confirm these study results. As well, Merck is conducting a study to assess switching individuals who are currently taking the TID regimen to the BID regimen.

* data are approximations based on visual observation of line graph charts