Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 14, Number 3/4, Spring 2000
Gil Shepard

In a late-breaker, Dr. Steve Deeks presented results from a prospective study of STIs in patients who were on protease inhibitor-based therapy and who had a viral load over 2,500 copies for at least twelve months (LB-10). Eighteen patients were randomized to discontinue therapy. They had about three years of protease inhibitor therapy and a detectable viral load for about 31 months (range, 28 to 33 months). Upon discontinuing therapy, mean CD4 count was 245 cells (range, 104 to 307), mean viral load was just below 40,000 copies (range, 10,000 to 100,000), and the median decrease in protease inhibitor susceptibility was 56-fold (range, 23 to 79). Viral load, CD4 levels and phenotypic resistance were measured weekly for the first 12 weeks, at which point therapy was restarted and tests were done every four weeks.

At 12 weeks, the median CD4 decrease was 94 cells (28 to 120) and the median viral load increase was 0.82 log (0.34-0.92). In 16 patients, the virus shifted to a protease susceptible (<2.5 fold decrease in susceptibility) phenotype — or wild-type virus — after two to 15 weeks (mean 8.5 weeks). Slower reversion to wild-type virus was associated with more protease inhibitor resistant mutations at baseline and with a smaller viral load reduction on therapy as compared to pretherapy viral load. Nucleoside analog resistance persisted in seven patients, but typically at a much lower level than at baseline. Replicative fitness (the ability of the virus to reproduce) increased from a median of 22.3% to 67.1% (p=0.004). Deeks noted that prior to the reversion to a wild-type virus, there was a slow decline in CD4 cell counts and a slow rise in viral load; however, after the shift CD4 counts dropped and viral load increased dramatically. He suggested that the former could be associated with residual antiviral activity and the latter with an increase in replicative fitness.

In four of eight patients who reverted to wild type, PBMC cultures (taken 12 to 36 weeks after discontinuing therapy) showed resistant virus that was identical to that at baseline. That is, while the virus in their blood had switched to protease inhibitor susceptible, resistant virus could still be found in PBMCs, which suggests that wild-type outgrew resistant virus but did not eliminate it. Moreover, it is possible that the other patients also still had resistant virus, even though tests could not detect it.

Researchers also looked at the fractional replacement rate of CD4 cells. Prior to interrupting therapy, the rate in those patients on "failing" therapy was 0.011/day, which was significantly lower than the rate of 0.032/day observed in patients who were not on therapy. This suggests that despite having a detectable viral load, those patients receiving drug treatment had a longer CD4 half-life than patients receiving no treatment. In addition, during STIs, there was a reduction in either CD4 half-life or CD4 production.

While Deeks did not draw any conclusions about STIs as a treatment option in this population, he did find evidence of continued antiretroviral therapy benefit even in cases where patients have resistant virus, which might be because the resistant virus is less fit than wild-type. This implies that, at least for patients with few or no treatment options, continuing drug therapy when viral load is detectable is more beneficial than discontinuing therapy altogether.

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