Fifty-four individuals were randomized to treatment- 36 into Arm A and 18 into Arm B. Forty-one of 54 completed 44-48 weeks of therapy and were included in the analysis and are described in . Thirteen subjects failed to complete the study, 8 subjects (22%) in Arm A and 5 (28%) in Arm B (p=1.0). Reasons for patient discontinuation included non-adherence with study medications/procedures (N=4), lost to follow up (N=3), protocol defined virologic failure due to non-adherence (N=2), adverse events (N=1), baseline resistance to LPV/rit (N=1), suicide (N=1), and investigator preference (N=1).
Baseline characteristics of 41 subjects completing the trial
Of the 41 patients completing the trial, 15 remained on their originally prescribed ARV regimen. Of the 26 changing therapy all remained on a potent ART regimen consisting of at least agents anchored by either efavirenz or a ritonavir-enhanced PI. There were no significant differences in changes between arms. Of 28 completing subjects in Arm A, 27 competed Cyclosporine A treatment. One subject terminated Cyclosporine A prior to completing week 1 due to nausea. Therapeutic levels were documented in 20 of 27 (74.0%) subjects by week 2 and 23 of 27 (85.2%) by week 3. Four subjects did not achieve target concentrations with 3 above target and 1 below. Mean Cyclosporine A levels in these 27 subjects in Arm A were 321, 431, 363, and 362 ng/mL at day 3, weeks 1, 2, 3 respectively.
Levels of plasma HIV-1 RNA were measured longitudinally in all patients (). A rapid and sustained reduction in plasma viremia was seen in all patients analyzed. The median time to HIV-1 RNA levels below detection (50 copies/mL) was 15 weeks in Arm A (IQR 12, 20) and 16 weeks in Arm B (IQR 12, 20) (p=0.58). Interestingly at week 4 there was a statistically significant higher viral load in the patients receiving Cyclosporine A, 3.37 log copies/mL versus 2.75 log copies/mL (p=0.041). This difference was not sustained and its significance is unclear. Proviral DNA levels were measured in CD4+ T cells in patients at weeks 12, 24 and 48 (). Levels could be quantified in 36 of 41 subjects. Quantification failed in 2 subjects and inadequate cells were available for analysis in 3 subjects. Among the 36 subjects in whom proviral DNA levels were analyzed, 24 were in Arm A and 12 in Arm B consistent with the 2:1 randomization scheme. There were no significant differences between levels of proviral DNA at weeks 12, 24, and 48 between treatment arms either expressed as median log10 copies per 106 CD4+ T cells (1.88 versus 1.92 p=0.84, 2.12 versus 1.96 p=0.34, 2.22 versus 2.13 p=0.70) or mean copies per 106 CD4+ T cells (130 versus 115 p=0.70, 105 versus 92 p=0.34, 95 versus 80 p=0.84). The mean differences (and 95% confidence intervals) between arms A and B in the change from baseline to weeks 12, 24, and 48, in log10 copies per 106 CD4+ T cells were: 0.05 (-0.33, 0.44), 0.08 (-0.24, 0.36), and 0.07 (-0.22, 0.36). When comparing Arms A to B there were no differences in proviral DNA levels at all time points. There was also no significant difference in the decay of proviral DNA from weeks 12 to 48 between arms, -0.14 versus -0.04 (p=0.99).
Fig. 1a. Longitudinal mean log10 HIV-1 RNA levels in patients completing the study.
Mean absolute CD4+ T cells counts did not differ between Arms A and B at baseline, weeks 2, 4, 12, 24, or 48 (p=0.24, 0.28, 0.43, 0.78, 0.75, 0.73 respectively) (). The increase in CD4+ T cell counts at week 48 were 301 and 295 in Arms A and B respectively (p=0.95). The levels of activation in the memory (CD45RA-) CD4+ T cell population were determined with both CD38 and HLA DR staining. There were no differences noted between arms. One measurable effect of Cyclosporine A was a marked and statistically significant reduction in absolute numbers of cells positive for Ki67 staining in the memory CD4+ T cell population at weeks 2 and 4 (11 versus 24 p=0.04 and 9 versus 25 p=0.01) consistent with the ability of Cyclosporine A to inhibit IL-2 induced T cell proliferation. A more striking difference was seen between treatment arms in Ki67 staining in the CD8+CD45RO+ population at weeks 2 (15 versus 66 p<0.001) and 4, (12 versus 49, p<0.001).