Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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GMHC Treatment Issues, Vol. 10, No. 2; February 1996
Theo Smart
The Old Guard Combinations
New data from various studies largely paralleled the previously reported results from ACTG 175 and Delta 1 trials (see last October's Treatment Issues, pages 2-4). Robert Schooley, M.D., presented data from a Burroughs Wellcome sponsored study of AZT versus AZT/ddC and AZT/ddI (abstract 202). The trial enrolled people with CD4 cell counts below 300 and less than four weeks of prior AZT. The primary goal was to see whether the addition of ddI (at half dose) or ddC delayed the development of resistance to AZT. They did not, but AZT/ddI was associated with a significantly enhanced suppression of HIV and extension of life as compared to AZT alone.
AZT/ddI also produced a significant survival advantage over AZT monotherapy in people with prior nucleoside analog experience in the Delta 2 study, now that more deaths have occurred during the long-term follow-up (abstract LB5). Most of the people who died had entered the study already diagnosed with AIDS.
The Community Programs for Clinical Research on AIDS (CPCRA) network sponsored the NuCombo study, which also compared AZT against AZT/ddI and AZT/ddC. For the trial cohort as a whole, NuCombo found only a marginal survival benefit for AZT/ddI after two years of observation (abstract LB4). The 1,113 participants in this study had more advanced disease status than those in Delta or ACTG 175. NuCombo participants entered the trial with an average CD4 cell count of 119.
In the subset of trial enrollees who were initially AZT-naive (about 23 percent of the total enrollment), combination therapy had a significant clinical benefit over AZT alone. There was no benefit to combination in the AZT-experienced patients. Combination therapy also was poorly tolerated, calling into question the wisdom of adding ddC or ddI to AZT in people with very advanced disease. For ddI, in particular, tolerance and compliance were lower because of gastrointestinal side effects.
Long-term follow-up of NUCA 3001 and 3002 (AZT/3TC studies in antiretroviral naive and experienced patients, respectively) shows that viral load and CD4 cell responses in the 3TC- containing arms at week 24 were sustained in a high proportion of persons who continued treatment out to 68 weeks in NUCA 3001 and 52 weeks in NUCA 3002 (abstracts 198 and 199). In NUCA 3002, no difference in clinical endpoints was seen between arms. The clinical endpoint differences in NUCA 3001 were not statistically significant.
Two posters addressed the effect or safety of 3TC in people with advanced disease. A French group evaluated two doses of 3TC combined with AZT in seventeen people with less than 50 CD4 cells (abstract 299). Both doses lowered viral load and increased CD4 cell counts. In eight patients at the month one timepoint, viral load decreased by more than 90% or became undetectable. This was sustained at month three in four trial participants. At month six, fifteen out of the seventeen 3TC- treated volunteers were alive, only one had had an opportunistic infection.
A Toronto physician, I. W. Fong, M.D., reported that 3TC is not as well tolerated in advanced HIV disease as in earlier stages of the disease and can cause serious side effects (abstract 134). His data came from 36 of his advanced patients enrolled in the 3TC compassionate use program (mean CD4 count at baseline was 80 cells). Fifteen took 3TC as a monotherapy, and the rest used it in combination with AZT, ddI or ddC. Seventeen patients reported serious side effects, with seven discontinuing 3TC as a result. Among the side effects were five cases of hair loss (13.9 percent), five cases of neuritis (13.9 percent), four cases of anemia (11.1 percent), four cases of leukopenia, or low white blood cell count (11.1 percent), including two cases of severe neutropenia (less than 500 of the infection-fighting neutrophil cells per mm3 of blood), and three cases of nausea and vomiting (8.3 percent). More side effects were reported on monotherapy (12 of the 21 events) than on combination treatment.
d4T and d4T/ddI
Christine Katlama, M.D., presented data from a placebo- controlled dose-ranging study of d4T (abstract 196). The trial enrolled 66 people with more than 350 CD4 cells (baseline median 527). Viral load (4.2 log or 15,900 copies/ml of plasma at baseline) decreased by 0.8 log (84 percent) on the high dose (80 mg per day), and 0.6 log (75 percent) on the low dose (40 mg per day). These reductions were sustained for the duration of the twelve week study. Average CD4 cell counts at week twelve were 35 cells over baseline on the high dose and twenty cells over baseline on the low dose. These increases compare with a decline of 45 cells in the placebo group, but the CD4 cell changes were not considered significant.
Forty patients continued with open-label low-dose d4T. Those who had been on placebo had a seventy percent reduction (one- half log) in viral load. The antiviral responses were sustained through month twelve, although viral load rose slightly in the patients randomized to high dose when crossed over to low dose d4T. During the follow-up period, there were nine cases of peripheral neuropathy, leading one patient to stop the d4T.
Meanwhile, Swiss researchers reported on a study in 23 persons with late-stage disease and a long history of prior nucleoside use (abstract 136). d4T had only a minor effect on viral load (0.2 log or 37.5 percent reduction) after one month, and that effect was lost by month three. As with the NuCombo study, this may be another case of a nucleoside analog not performing well in heavily pretreated patients. Finally, the results reported on the antiviral activity in an ongoing study of the combination of d4T with ddI (abstract 197) were less robust than reported to activists last November (see the November, 1995 Treatment Issues, page 3). The data from this trial is in a constant flux as more people reach later timepoints.
Ninety-four patients have been randomized into the study; 71 are evaluable at present. Viral load responses were presented only for 54 people who entered the study with plasma viral load of over 1,000. The median CD4 cell count in these 54 patients was 310 (average CD4 count: 327), and the median viral load was 4.6 log (39,800 copies/ml). The median CD4 cell count at entry in all 71 evaluable patients was slightly higher at 325 (the average was 336).
More than half of the study participants have had at least 28 weeks of treatment. The average reduction in viral load was 1.4 log (96 percent) in the 32 on treatment at week 28. Contrary to appearances last November, the average viral load response is not increasing over time, but it was sustained at 1.5 log (97 percent) below baseline in the fourteen patients with measurable viral load that have completed 52 weeks of treatment. So far, there have been no statistically significant differences between the various dose arms of the study. The variation in individual response was great, though, with reductions in viral load ranging between 0.29 log (50 percent) and 2.9 log (99.8 percent).
Overall, 26 patients have completed 52 weeks of treatment and their CD4 counts are up by a mean of 68. At present, there appears to be a CD4 response favoring the high dose. Counts increased by 141 cells in the four on this arm at week 52, as opposed to a loss of more than twenty cells on the low dose. Again, these as yet nonsignificant differences are sure to change as more people complete the study.
d4T and ddI both cause peripheral neuropathy as a side effect, but only one episode has been noted in this trial. Six patients discontinued therapy due a variety of other side effects, including increases in liver function tests, abdominal pain, neutropenia and depression.
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