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Efficacy and tolerability of 10-day monotherapy with SPD574 (apricitabine) in antiretroviral-naive, HIV-infected patients
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AIDS: Volume 20(9) 12 June 2006 p 1261-1268
Cahn, Pedroa; Cassetti, Isabelb; Wood, Robinc; Phanuphak, Praphand; Shiveley, LeeAnne; Bethell, Richard Cf; Sawyer, Jamesg
From the aFundacion Huesped, Buenos Aires, Argentina
bHelios Salud, Buenos Aires, Argentina
cThe Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa
dThai Red Cross Aids Research Centre (TRCARC), Pathumwan, Bangkok, Thailand
eShire Pharmaceutical Development Inc., Wayne, PA USA
fShire Biochem Inc., Laval, Quebec, Canada
gPrism Ideas, Nantwich, Cheshire, UK.
Abstract
Objective: Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development for patients with HIV disease. This study evaluated the antiretroviral efficacy, tolerability and safety of apricitabine monotherapy, administered for 10 days in antiretroviral-naive, HIV-1 infected adults.
Methods: Adult patients (≥ 18 years) with HIV infection (CD4 count ≥ 250 cells/μl; plasma HIV-1 RNA level 5000-100 000 copies/ml) were randomized to 10 days' double-blind oral therapy with placebo or apricitabine 400 mg/day, 800 mg/day, 1200 mg/day, or 1600 mg/day.
Results: At 7 days, all apricitabine doses produced statistically significant log10 reductions in plasma HIV RNA levels from baseline relative to placebo (n = 13; P < 0.0001), as follows: -1.16 (400 mg; n = 11), -1.28 (800 mg; n = 12), -1.44 (1200 mg; n = 14), -1.30 (1600 mg; n = 13). After 10 days, the log10 viral load reductions with apricitabine 1200 mg (-1.65; P = 0.01) and 1600 mg/day (-1.58; P = 0.04) were significantly greater than that with the 400-mg dose (-1.18). No clinically relevant changes were observed in CD4 or CD8 cell indices. Apricitabine was well tolerated and showed no tendency to select any particular resistance mutation.
Conclusion: Apricitabine monotherapy showed promising antiretroviral efficacy, good tolerability and a low propensity for resistance selection in antiretroviral-naive HIV-infected patients treated for 10 days. These results warrant further evaluation of the long-term clinical efficacy and tolerability of apricitabine.
Introduction
There is continuing need for new antiretroviral agents of existing classes that address problems of cross-resistance and poor tolerability, especially for patients who have received previous courses of therapy [1].
Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor (NRTI) in clinical development for patients with HIV disease. Apricitabine has additive or slightly synergistic antiviral activity in combination with other antiretroviral agents in vitro [2], with the exception of other deoxycytidine analogues that compete with apricitabine for intracellular activation by phosphorylation [3]. Apricitabine has shown good activity in vitro against HIV-1 strains resistant to lamivudine and other NRTI [2,4]. Apricitabine retains a substantial proportion of its antiviral activity against HIV-1 containing multiple thymidine analogue mutations (TAM), with or without the M184V mutation [4]. This promising in vitro profile suggests that apricitabine may be of clinical utility for the treatment of patients who have failed previous regimens including lamivudine or emtricitabine.
In healthy volunteers, single doses of apricitabine (400-1600 mg) showed linear pharmacokinetics, with an elimination half-life supportive of twice daily dosing [5]. Apricitabine was well tolerated in volunteers [5] and in vitro studies suggest the drug has a low potential for cellular or mitochondrial toxicity [2]. Aprictabine is a single (-)-enantiomer [6,7] that shows no racemization in vivo [5]. Previously, monotherapy with a racemic 50: 50 mixture of apricitabine with the equipotent (+)-enantiomer administered over 7 days produced viral load reductions of > 1.0 log10 HIV-1 RNA copies/ml in antiretroviral-naive patients [8].
This 10-day study evaluated the antiretroviral efficacy and tolerability of four different total daily doses of apricitabine monotherapy (covering six dosing regimens) in antiretroviral-naive, HIV-1 infected patients.
Discussion
The dose and frequency of antiretroviral treatment required for maximum viral suppression must be balanced against possible dose-related toxicity and pill burden in order to promote long-term patient adherence. Therefore, the development of a new antiretroviral should include early studies of efficacy in relationship to dose, tolerability, and frequency of dosing.
This study evaluated a range of apricitabine doses and dosing regimens. A 10-day monotherapy design provided a direct and expedient measurement of the short-term safety and potential efficacy of apricitabine, while limiting the potential for the development of antiretroviral resistance. Monotherapy administration to antiretroviral-naive HIV-infected patients allows direct characterization of the potency, safety, and tolerability of an investigational drug without the confounding factors of other active agents or baseline resistant viruses [1].
All apricitabine doses administered in this study produced statistically significant reductions in HIV-1 viral load relative to placebo after 7 days of treatment. After 10 days, apricitabine doses of 1200 and 1600 mg/day gave mean viral load reductions of -1.65 and -1.58 log10, respectively, both of which were significantly greater than the reduction seen with 400 mg/day. This pattern was reproduced in a numerical trend in the proportions of patients with a reduction in viral load of ≥ 0.7 or ≥ 1.0 log10, and in the mean slope of viral load decline over time. These data characterize a dose-response curve for apricitabine that appears to reach a plateau at the 1200 mg and 1600 mg daily doses. There was no significant difference in efficacy between the once- and twice-daily dosing regimes tested. The expected return of viral load levels to pre-treatment levels upon treatment cessation indicates that the observed antiviral effects were due to the activity of apricitabine.
Viral load reductions seen with the higher doses of apricitabine are similar to those produced by other recently marketed NRTI in monotherapy trials in antiretroviral-naive HIV-infected patients. In a small, non-controlled study, the nucleotide analogue, tenofovir (300 mg once daily) produced a mean viral load reduction of approximately 1.5 log10 at 21 days [10]. In a randomized, open-label study in patients naive to lamivudine or abacavir, the cytidine analogue, emtricitabine (FTC; 200 mg once daily) gave a mean 1.7 log10 reduction at 10 days [11].
All apricitabine doses were well tolerated, with no severe or serious adverse events and none that lead to treatment discontinuation. The overall reporting of adverse events was relatively high owing to the admission of subjects into the clinic throughout the study. However, apricitabine showed a tolerability profile similar to placebo in terms of the nature and incidence of adverse events reported. Clinically significant improvements in the CD4 cell count would not be expected following 10 days of treatment, and were not observed in the present study. Some studies have noted reductions in CD4 cell counts over short periods of NRTI treatment that might reflect myelotoxicity [12]. In this study, the CD4 cell count at 10 days was lower in the apricitabine 1600 mg/day group than in the 400 mg/day group. However, there was no apparent dose relationship and this finding appears anomalous. Data from in vitro studies suggest that apricitabine has a low potential for myelotoxicity [2].
This study offered the first opportunity to assess the clinical resistance profile of apricitabine, albeit during short-term therapy. Notably, HIV-1 mutations associated with NRTI resistance were identified in four patients (6.4%) at baseline. The most likely explanation of these observed mutations is that patients were infected with NRTI-resistant virus. The frequency of these mutations is consistent with reported rates of genotypic resistance of 10-20% in antiretroviral-naive, HIV-infected subjects in North America and Western Europe [13-17]. Apricitabine retains antiviral activity against NRTI-resistant HIV-1 containing TAM, and its activity is little affected by the M184V mutation commonly selected by lamivudine [4]. The similar response to apricitabine observed in the present study in patients with mutant and wild type HIV-1 at baseline adds to evidence suggesting that apricitabine may have a promising role in the management of antiretroviral-experienced patients.
There was no evidence that apricitabine selected for any particular mutation during 10 days of monotherapy at any dose. No new mutations arose in viral reverse transcriptase sequences from patients during the 10-day treatment period. One mutation known to be associated with NRTI resistance arose from a pre-existing mixture in a single patient treated with apricitabine, but this occurred after the end of study therapy. Apricitabine-triphosphate (the active metabolite) has an intracellular half-life in peripheral blood mononuclear cells of 6-7 h [18]. Its cellular concentrations, and hence the selection pressure for resistance, are expected to drop rapidly after treatment cessation. Therefore, it seems most likely that any changes observed after the 10-day treatment period reflected minor fluctuations in a mixed population of viruses in these patients, coupled with the low level of precision with which the assay was able to determine the composition of mixtures present in the samples.
In conclusion, monotherapy with apricitabine showed promising antiretroviral efficacy, good tolerability and a low propensity for resistance selection in antiretroviral-naive HIV-infected patients treated for 10 days. These results warrant further evaluation of the long-term clinical efficacy and tolerability of apricitabine in patients failing treatment with other deoxycytidine analogues such as lamivudine and emtricitabine.
Results
Patients
Sixty-four patients were enrolled: 55 from Argentina, six from South Africa and three from Thailand. One was not randomized (because of a urinary tract infection), leaving a randomized ITT population of 63 patients: 13 placebo and 50 apricitabine. One randomized patient (apricitabine 1600 mg/day) was withdrawn on day 4 for reasons of ineligibility, leaving 62 patients who completed all 10 days of treatment.
The ITT population had a mean (± SD) age of 33.9 (± 8.73) years; 57% were male and 43% female (Table 1). At baseline, the mean (± SD) log10 HIV-1 RNA level was 4.3 (± 0.40) copies/ml. The mean CD4 and CD8 cell counts were 505.7 (± 190.07) cells/μl and 1073.7 (± 409.57) cells/μl, respectively. These variables were similar across the treatment groups (Table 1).
Treatment compliance was 100% for all treatment groups except for the 800 mg 12-h group, in which it remained ≥ 95% despite the withdrawal of the ineligible patient.
Viral load
For each daily dose of apricitabine, a statistically significant reduction in viral load was evident after 3 days of dosing (P = 0003). After 7 days, all daily doses produced statistically significant reductions in plasma HIV RNA levels from baseline relative to placebo (P < 0.0001; Table 2). The log10 mean reductions in viral load relative to placebo were as follows: -1.16 (400 mg), -1.28 (800 mg), -1.44 (1200 mg), -1.30 (1600 mg). Viral load reductions increased between 7 and 10 days and remained statistically significant for each daily dose (P < 0.0001 versus placebo at the end of treatment; Table 2). Fig. 1 shows the changes in viral load in each dose group over time.
Pair-wise comparisons showed no significant differences in the viral load reductions between the apricitabine daily doses after 7 days. After 10 days, the mean viral load reductions with the 1200- and 1600-mg doses were significantly greater than that with the 400-mg dose (P = 0.01 and P = 0.04, respectively; Table 2). Within-group comparisons showed no statistically significant difference between mean viral load reductions with 1200 mg once daily (-1.18) and 600 mg twice daily (-1.44; P = 0.067), or between 800 mg once daily (-1.23) and 400 mg twice daily (-1.23; P = 0.938). All regimens were significantly more effective than placebo (0.01 ≦ P ≦ 0.0009).
Significantly more patients in each apricitabine dose group had viral load reductions of ≥ 0.7 and ≥ 1.0 log10 HIV-1 RNA copies/ml after 7 and 10 days of treatment, as compared with placebo (P ≥ 0.001). There were no statistically significant differences between apricitabine groups. However, after 7 days, numerically more patients in the 1200- and 1600-mg/day groups (100%; P < 0.0001 versus placebo) showed a reduction of ≥ 0.7 log10 copies/ml, as compared with the 400 mg (81.8%) and 800 mg/day (83.3%) groups. A similar relationship was observed after 10 days, with 85.7% and 91.6% of patients treated with 1200 or 1600 mg/day, respectively, achieving a reduction of ≥ 1.0 log10 copies/ml (P < 0.0001 versus placebo; Table 2).
ANOVA analysis showed statistically significant reductions in the DAVG8 and DAVG11 values in the apricitabine groups versus placebo (P < 0.0001), but no significant differences between apricitabine doses (data not shown).
The overall mean daily rate of decline of viral load over 10 days in the apricitabine groups ranged from -0.09 to -0.15 log10 HIV RNA copies/ml/day (Fig. 2; P = 0.0002 to 0.0014 versus placebo). The rate ranged from -0.15 to -0.19 log10 HIV RNA copies/ml/day during the first 7 days of treatment (P = 0.0002 to 0.0012 versus placebo). No statistically significant difference in the rate of viral load decline was seen between the apricitabine and placebo treatment groups from day 8 to day 11. However, there was evidence of continued fall in viral load during this period for the three highest dose groups (-0.04 to -0.07 log10 HIV RNA copies/ml/day; P ≥ 0.08).
Viral load returned to pre-treatment levels following treatment cessation (Fig. 1). The mean increase in viral load ranged from 0.07 to 0.12 HIV-1 RNA log10 copies/day among the active treatment groups.
CD4 and CD8 cell counts
After 10 days' therapy, changes from baseline in LS mean CD4 cell counts (± SE) were as follows: +128.8 (± 54.0) cells/μl with apricitabine 400 mg/day); +29.5 (± 53.7) cells/μl with 800 mg/day; +82.8 (± 46.2) cells/μl with 1200 mg/day; +21.5 (± 52.8) cells/μl with 1600 mg/day, and -7.0 (± 47.7) cells/μl with placebo. Changes in LS mean CD8 cell counts ranged from +151.8 (± 112.4) cells/μl with 400 mg/day to +339.7 (± 95.9) cells/μl with 1200 mg/day in the apricitabine groups versus +96.5 (± 95.6) cells/μl with placebo. No clinically relevant changes were observed in CD4: CD8 ratios, or in any of these indices at day 24.
Tolerability and safety
The safety population comprised all 63 randomized patients. In total, 46 apricitabine recipients (92.0%) and 12 placebo recipients (92.3%) reported adverse events. No severe or serious treatment-emergent adverse events were observed, and none caused discontinuation of treatment or lead to death.
Thirty-nine patients (78.0%) treated with apricitabine, and nine (69.2%) who received placebo, reported adverse events deemed possibly related or probably related to study drug (Table 3). Headache, the most common such adverse event, was reported by 42.0% of apricitabine recipients. The frequency of headache appeared to show a dose relationship, although the incidence in the placebo group was also relatively high (30.8%). Nasal congestion appeared slightly more common with apricitabine than with placebo. Increases in serum amylase occurred in six patients treated with apricitabine, but these appeared to represent intra-subject variability. Other changes included low-level changes in lipase levels that occurred in a similar proportion of patients treated with placebo (3/13; 23.1%) or apricitabine (10/50; 20.0%). Otherwise, there were no clinically significant effects of treatment on vital signs, clinical laboratory tests, or on ECG results. More patients reported myalgia on apricitabine (5/50, 10.0%) than on placebo (0/13, 0%). However, these events were not considered related to apricitabine and their clinical significance is unclear.
There were no changes to patients' HIV classifications during the course of the study.
Genotyping
Four patients had viral mutations associated with resistance to NRTI at baseline. In one case, there was evidence of reversion from a primary TAM, as evidenced by the presence of T215S. In the other three cases, the HIV-1 reverse transcriptase genotype was L74V, V75M, or T215F and M41L. Three of these four patients received active treatment and in each case the reduction in viral load observed after 7 and 10 days was within the range seen for the remainder of patients allocated to the same treatment group (data not shown).
Sequence changes associated with NRTI resistance were observed in two patients during the study, one in the placebo group and one in the apricitabine 400 mg/day group. In the latter case, the observed genotype encoded a mixture of valine and methionine at days 1 and 11 (V75V/M), but was exclusively methionine at day 17. Since this change occurred after the end of study treatment, it is unlikely to be related to exposure to apricitabine. The sequence changes observed in nine other patients were not historically associated with drug resistance and probably reflected the presence of polymorphisms in the HIV-1 circulating in the study population. V118I or A62V, which were observed some patient samples in the absence of any other NRTI-associated mutations, are associated with multiple nucleoside-associated mutations (NAM) in treatment-experienced patients but are not considered to confer NRTI resistance themselves.
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