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

A phase I/II study of 3TC (AKA BCH 189) in people with ARC or AIDS was begun in September of 1991. This drug is another nucleoside analogue, having its effect on the reverse transcriptase enzyme, acting as a chain terminator. It is active against both HIV-1 and 2 and is active against AZT resistant virus. Synergism has been demonstrated with AZT while an additive effective has been seen with ddI and ddC. Ninety-seven people were enrolled with a mean CD4 count of 172 (all individuals had less than 300 CD4 cells). This was a monotherapy trial as all other antivirals were stopped 21 days prior to enrollment, although prior use was okay. There was weight gain or stabilization at all dosages. Significant improvement in CD4 counts were not observed at the 20 mg/kg/day dosage. However, the majority of participants had stabilization of their CD4 counts through week 24 at all dose levels. Forty-three of the 97 individuals had a positive p24 antigen at entry. Significant, sustained decreases (greater than 50% from baseline) were seen in four of seven and only at the 20 mg/kg/day dosage through week 12. The mean time to develop resistant virus was six months, and was found sooner rather than later, in those with less than 100 CD4 cells.

A phase I/II study was conducted in Frankfurt on 120 people using AZT and L697,661 as monotherapy and in combination. L697,661 was given three times a day with food as it has been found that bioavailability increases 10-fold when taken with food. The mean CD4 cell counts were 348-362 in all four treatment arms with all individuals having between 200-500 CD4 cells. Individuals were excluded if they had ever had greater than 60 days of prior AZT therapy. The study lasted for 48 weeks, had 30 people in each treatment arm - six each of whom were p24 antigen positive. The four arms were: AZT at 300 mg/day, AZT at 300 mg/day & 661 at 300 mg/day, AZT at 300 mg/day & 661 at 600 mg/day, and 661 at 600 mg/day. Fatigue occurred in 30% of people in each treatment arm. CD4 counts were stabilized in all groups with no difference found between the groups. Progression to AIDS or death was the same in all groups. Eleven of 30 people in the 661 monotherapy arm showed high level resistance (the 181 mutation). Low level resistant virus was seen in all three arms containing 661. Combination therapy prevented the development of the 181 mutation, determined to be the cause of high level resistance seen in all of the early trials with this class of drugs when given as monotherapy.

ACTG 213, use of oral RO-24-7429, a tat antagonist, was reported on in 96 people. tat, a gene found in the long terminal repeat (LTR) region of HIV, leads to the initiation of viral replication when activated. Without tat activation, LTR activity is at a very low level. This compound is a benzodiazapine derivitive, has activity in chronically infected cell lines, and has increased activity when given with food. Each of the four treatment arms contained 24 individuals. The four treatment arms were as follows with dosing every eight hours: 25 mg, 50 mg, 100 mg, or either AZT or ddI in standard dosages. People with 50-500 CD4 cells were included in the trial and prior antivirals were okay after a one month "wash-out" period. Eighty-three percent of the individuals completed eight weeks of treatment. The only serious adverse effect was a rash which occurred in 24% of participants. The development of the rash was dose related. All three treatment arms using the tat antagonist showed a decrease in the CD4 count from baseline, and no decrease or stabilization of p24 antigen levels (as compared with the group taking the nucleoside analogue) which did show decreases in p24 antigen levels. No antiviral effects have been seen in quantitative PBMC microculture and other virologic assays although plasma levels are still pending.

A phase I study of A-77003, an HIV protease inhibitor, was reported on. Due to the short half-life of the drug in the bloodstream, intravenous administration via a continuous drip was employed. Individuals with 200- 500 CD4 cells and no antiviral treatment within three weeks prior to the start of this trial were enrolled. Dosages were (mcg/kg/hr): 35, 70, 140, or 280. At the highest dose, the half-life was calculated at 35 minutes. There was no change in CD4 counts, p24 antigen levels, or quantitative PBMC culture. A decrease in plasma viremia in quantitative plasma cultures, was seen just after each infusion. The investigators claim that the current formula is not suited for infusion due to its vein irritating effect.

The next three reports are from a phase I/II dose ranging study of the safety and activity of RO-31-8959, an HIV protease inhibitor. These studies occurred in both previously AZT-treated individuals and in those with no prior treatment. Protease inhibitors prevent viral maturation.

The first of these took place in France in individuals with advanced disease with CD4 counts between 50-250. All participants had had prior antiviral treatment with a mean duration of prior AZT use of 400-500 days. The mean CD4 cell count was 130-150 at entry. There were three dosages employed in the trial all given three times/day: 75 mg, 200 mg, and 600 mg. During the 16 weeks of the trial, the drug was well tolerated with no bad side effects. There was an increase in mean CD4 cell count only at the 600 mg dose level, and this was statistically significant when comparing the 200 mg dose to that of 600 mg. The maximum increase in CD4 cells at the 600 mg dosage occurred at four weeks. There was a trend, which was not statistically significant, in decreasing p24 antigen levels seen from baseline at the highest dosage which was not seen at the two lower doses. Other quantitative viral assays such as PBMC and plasma cultures did not show any decrease in viral titer over time with any of the three dosages.

The trial which occurred in the United Kingdom also lasted 16 weeks but took place in minimally symptomatic or asymptomatic persons with less than 500 CD4 cells and no prior antiviral treatment. Forty-nine individuals were enrolled into one of four dosages: 25 mg, 75 mg, 200 mg, or 600 mg. The drug was well tolerated with no serious side effects. Changes in baseline CD4 counts was similar to the results obtained by the French: mean increases only in the 600 mg dose (seen until week four) and decreases seen in the other three doses. These differences in the counts were only trends and not statistically significant. With regard to their quantitative PBMC cultures, the investigators defined someone who was a "maintained responder" to the drug as one who had a greater than one log decrease in viral titer over time while on drug. The percentage of "responders" at each dosage level is as follows: 25 mg = 8%, 75 mg = 17%, 200 mg = 25%, and 600 mg = 33%.

The third trial with this agent took place in Italy in persons with advanced disease (less than 300 CD4 cells) without prior AZT use. The mean CD4 count was about 160 in all treatment groups. There were five treatment arms: 75 mg protease inhibitor (PI) & AZT, 200 mg PI & AZT, 600 mg PI & AZT, 600 mg PI alone, and AZT alone. The drug was well tolerated in all groups. CD4 cell counts increased above base line in all five treatment arms for 16 weeks, although the combinations of 200 mg & AZT and 600 mg & AZT showed the best results in this regard. However, due to the small number of participants in each study arm, only trends were seen and not statistically significant increases. Other viral parameters are in progress.

In a phase 1C study report from San Francisco, high dose GLQ 223 was administered to people with ARC at SF General Hospital or St. Francis Hospital in conjunction with Gene Labs of Redwood City, CA. In vitro activity of GLQ 223 has previously been established in chronically infected macrophages, acutely infected T lymphoblastic cells, and in PBMCs from HIV infected people. In a quick review of past trials, phase 1A, 18 individuals received a single intravenous bolus of drug up to 36 mcg/kg. In phase 1B, 54 participants experienced dose escalation up to 50 mcg/kg. Some individuals in this group had dose escalations up to 200 mcg/kg as inpatients. In the current phase 1C trial, nine individuals from the phase 1B trial who had had their dosage escalated to greater than 150 mcg/kg and wished to increase it further were eligible if they had no active OI and had no history of severe allergic reaction to the compound. The dose was increased in 50 mcg increments to 500 mcg/kg. The duration of the study was six months. A commonly reported "flu-like" illness and elevations in CPK levels was seen through the fourth infusion. There were acute allergic reactions seen in five of nine individuals with three of them being "severe." All of these responded to conventional treatment for these reactions. Five participants did not complete the study. Four of nine had increases in CD4 cells while the other five individuals reported decreases in their counts. Weight gain occurred in seven. Just a reminder, phase I dose escalating trials are not usually designed to look at the question of efficacy. A phase II trial which is nearing completion, will hopefully yield answers to this question. This latter trial is occuring at six sites around the USA and is measuring the effects of GLQ 223 vs. GLQ 223 & AZT vs. AZT. The dosage being used in this trial is 150 mcg/kg every three weeks.

In an interesting non-drug trial conducted in Munich, the role of physical exercise in the treatment of people with HIV disease was assessed. The trial lasted just three months and enrolled 49 male and female participants in all stages of HIV disease, including aids. The participants were not randomized but were placed into the exercise or control group based on their current exercise habits. Exercise had to occur at least twice/week for at least one hour each time in the exercise group. There were five OIs and two deaths in the control group while there were no OIs or deaths in the exercise group. There was no statistically significant improvement in CD4 cell counts or mental status as gauged by commonly used personality and mental status tests. However, there were trends seen of elevated mood and improved mental status in the exercise group as compared with the controls. Anxiety was decreased in the exercise group compared with the controls. Although one could argue that since there was no randomization of the participants, that self selection occurred, with those already of poorer health either unable or unwilling to exercise, participating in the control group. Also, the type of exercise was not stipulated, which could have important implications. Nonetheless, these results are interesting enough to suggest that a randomized clinical trial should be undertaken to ascertain whether there is benefit in exercise to people with HIV disease.

References

1. WS B26. 1993. IX International Conference on aids. Berlin, Germany. June 1993.

2. WS B29 (4,5). 1993. IX International Conference on aids. Berlin, Germany. June 1993.
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