Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Joel Gibson, MS

In November of 1991, it was announced that the two NNRTI which were in clinical trials at that time as monotherapy, rapidly developed resistance within four to eight weeks. However, prior to the development of resistance, strong, effective antiviral effects were seen in lab markers, e.g. p24 antigen. Some drug manufacturers just as rapidly dropped all future plans for their NNRTI. However, BI continued to study Nevirapine and to plan future trials in the US and Europe using drug combinations.

A few months back, BI held a seminar designed to relay information to the HIV affected community regarding their progress and experience with the use of Nevirapine. The majority of the presentation was given by Maureen Myers, PhD, Director of Clinical Research in virology. She spent the first portion of her talk on the results of both NVP monotherapy and in combination with AZT (ACTG 164 and 168 respectively). Both studies had participants with prior AZT usage. In dosages ranging from 12.5 mg/day to 200 mg/day or 400 mg/day, decreases in p24 antigen were seen by seven to 14 days after initiation of therapy. This initial decrease in p24 antigen was greater at 200 mg/day than from 12.5 or 50 mg/day and greater still and more prolonged when accompanied by AZT. In a small number of participants who took increased doses up to 600 mg/day, decreases in p24 antigen levels were still apparent at 24 weeks of study. Their definition of a decrease in p24 antigen level is: greater than 50% decrease from the baseline p24 antigen level and occurring in greater than 50% of the study participants.

In a small international study conducted in Australia and in The Netherlands, dosaging issues with regard to concurrent use of AZT and NVP vs. an alternating schedule of both drugs, shed more light on the best administration for maximum benefit. In ACTG 208, the question of whether the development of resistance would be slower in people with greater than 500 CD4 cells sought to be answered. Also the benefits of increasing the dose to 400 mg/day after an initial two to four week period at 200 mg/day vs. beginning therapy at 400 mg/day was explored in relation to the development of adverse side effects. Both dosing groups exhibited a mean increase in CD4 cells for six months (both in absolute number and percentage), albeit there was a very small number of participants in this trial.

BI's longest running triple drug treatment trial began in November of 1992 at the University of Alabama in Birmingham. Seventeen of 24 participants have been recruited as of 3/18/93 into one of four treatment arms: concurrent NVP and ddI, alternating NVP and ddI, NVP and AZT and ddI, and NVP and AZT and ddC. ACTG 241 which is currently recruiting at roughly 16 sites throughout the USA, (but not in Seattle), is to comprise a total of 400 patients when fully recruited. This study was initially to have just 200 participants at 10 sites until the recent expansion of the trial occurred in February/March of this year due to an article appearing in Nature1.

The most common adverse side effect is a non-pruritic rash which occurs within the first 21 days of therapy. This rash is more common at the 400 mg/day dosage. However, within this group it is much less common when NVP is given in a two to four week "lead in" dose of 200 mg/day. Increases in SGOT, SGPT, and Total Bilirubin were seen equally at the 200 mg/day and the 400 mg/day dosages (21 vs. 22 of 110 patients). Being a benzyl diazapine derivative, fatigue and/or somnolence was a potential concern. However, no one required drug discontinuation due to these reasons.

As far as resistance is concerned, changes in the viral codon (genetic code) are seen at all doses of NVP. There are multiple codon changes which lead to resistance. These specific changes are being delineated. Larder suggested that some viral mutations which lead to NVP resistance may lead to increased AZT sensitivity.2 If true, this might diminish the appeal of convergent therapy. BI is not putting all its hope for this drug in the concept of convergent therapy. They also feel that its potential role as an effective antiviral in combination therapy, is still be explored (See following article).

In conclusion, BI has expressed a willingness to directly inform and solicit commentary from the HIV affected communities. However, even with the presentation of this appealing data, important issues remain to be resolved. The use of the newer immune complex dissociated (ICD) p24 antigen assay, albeit better than the standard p24 assay, is still lacking in sensitivity and can only be used in groups of patients with a positive p24 antigen. CD4 counts are becoming more suspect as an indicator of drug efficacy. Other virologic assays should be done with these studies to more convincingly demonstrate an antiviral effect. The rapid development of resistance is still of concern until it can be proven otherwise by combination trials. Also, in all of the trials mentioned, the number of participants was very small. Therefore, extrapolations regarding efficacy to the community at large await the results of large scale trials, further virologic data, and the demonstration of decreased development of resistance compared with earlier trials. BI is committed to conduct some trials in populations which have less than 50 CD4 cells. It also has stated enthusiastic support for other ACTG trials which seek to incorporate NVP into some combination of drug therapy.

References

1. Y-K Chow, et al. 1993. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature 361:650-653.

2. B.A. Larder. 1992. 3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrobial Agents and Chemotherapy 36:2664-2669.
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