Preliminary genotypic analysis showed that the majority of baseline mutations in patient HIV isolates were nucleotide excision mutations (NEMs) and associated mutations occurring at sites 41, 65, 67, 70, 74, 151, 184, 210, 215, and 219. The proportions of subjects with >= 1 NEM and associated mutations were 76% (26 of 34), 68% (19 of 28), and 87% (20 of 23) of subjects in the atazanavir 400-mg and 600-mg and ritonavir groups, respectively. Eighty-one percent (69 of 85) of randomized subjects had no primary PI mutations (sites 48, 82, 84, 90) at baseline. No subjects had >= 4 primary PI mutations. Primary and secondary mutations [>= 4 at sites 10, 20, 24, 33, 36 (atazanavir subjects only) 46, 48, 54, 63, 71, 73, 82, 84, 90] were identified at baseline in 21% (seven of 34), 18% (five of 28) and 13% (three of 23) of subjects in the atazanavir 400-mg and 600-mg and ritonavir groups, respectively.
For the initial NRTI combination, the majority of subjects (78%) used a stavudine-containing backbone, either stavudine plus didanosine (67%) or stavudine plus lamivudine (11%). At 24 weeks, mean declines (± SE) in plasma HIV-1 RNA levels from baseline for subjects in the atazanavir 400-mg, atazanavir 600-mg and ritonavir groups were 1.28 ± 0.20, 1.11 ± 0.20 and 1.50 ± 0.31 log10 copies/ml, respectively. At 48 weeks, these mean changes were 1.44 ± 0.25, 1.19 ± 0.22 and 1.66 ± 0.23 log10 copies/ml, respectively (Fig. 1a). The proportions of randomized subjects with a virological response at 48 weeks were comparable across groups, specifically, 41% (14 of 34), 29% (eight of 28) and 35% (eight of 23) in the atazanavir 400-mg and 600-mg and ritonavir groups, respectively (Fig. 1b). The differences in efficacy measures between treatment groups were not statistically significant (P = NS). Mean CD4 cell changes from baseline at 48 weeks in the atazanavir 400-mg, atazanavir 600-mg and ritonavir groups were 109, 55 and 149 × 106 cells/l, respectively (Fig. 1c). Some of the differences in changes observed in the HIV-1 RNA levels and CD4 cell counts can be explained, in part, by the substantial differences in dropout rates across the three groups (see below).
Among subjects with >= 1 NEM and associated mutations at baseline, the proportions of subjects with HIV-1 RNA < 400 copies/ml at week 48 were 42% (11 of 26), 32% (six of 19) and 45% (nine of 20) in the atazanavir 400-mg and 600-mg and ritonavir groups, respectively. The number of subjects with >= 4 primary and secondary PI mutations at baseline (2, 0, and 1 in the atazanavir 400-mg and 600-mg and ritonavir groups, respectively) was too small for meaningful comparison of virological response at week 48.
Safety and tolerability
Overall, 33% of randomized subjects (28 of 85) discontinued therapy before 48 weeks. The rate of discontinuation was higher in the ritonavir group than in the atazanavir 400-mg and 600-mg groups (52, 24 and 29%, respectively), and more discontinuations due to adverse events were reported in the ritonavir group than in the atazanavir 400-mg and 600-mg groups (30, 9 and 11%, respectively). The proportion of subjects discontinuing treatment because of adverse events that were at least possibly related to the study medication was also greater in the ritonavir group than in the atazanavir 400-mg and 600-mg groups (26, 12 and 11%, respectively). After 48 weeks, only two subjects discontinued treatment because of an adverse event. Other reasons for treatment discontinuation were comparable between the groups. Among the 82 subjects who received study medications the mean duration of therapy was longer in the atazanavir groups than in the ritonavir group (42 versus 32 weeks). No deaths reported during the study.
The overall incidence of serious and non-serious adverse events was comparable across groups, ranging from 12 to 14% for serious events and from 91 to 93% for non-serious events. Clinical adverse events and laboratory abnormalities reported as adverse events, and which occurred in at least 15% of patients in any group, are shown in Table 3. Diarrhea and nausea were more common in the ritonavir group. Jaundice occurred only in the atazanavir groups. Grade 1 or 2 scleral icterus was reported in one subject (3%) in the atazanavir 400-mg group, two subjects (7%) in the atazanavir 600-mg group and one subject (4%) in the ritonavir group. Lipodystrophy was reported as a clinical adverse event in two subjects (7%) in the atazanavir 600-mg group and two subjects (9%) in the ritonavir group. These were reported as grade 1 to 2 disease, although there is currently no case definition for lipodystrophy.
Grade 3 to 4 laboratory abnormalities are summarized in Table 3. Grade 3 to 4 elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were more frequent in the ritonavir group. Grade 3 to 4 elevations in total bilirubin values were more frequent in the atazanavir groups but were not associated with grade 3 to 4 elevations in transaminase values. Hyperbilirubinemia in the atazanavir groups was predominantly unconjugated (indirect) and was reversible, asymptomatic and dose related.
The lack of adverse effects from atazanavir on plasma lipids was significantly different from the changes in serum lipid profiles seen with ritonavir. Mean baseline values for total cholesterol, fasting LDL-cholesterol and fasting triglyceride concentrations are presented in Table 2, and changes from baseline to 48 weeks are shown in Figure 2. At 48 weeks, mean changes in lipids in the atazanavir 400-mg and 600-mg and ritonavir groups were as follows: total cholesterol, 1.0, -5.1 and 10.7%, respectively; fasting LDL-cholesterol, -0.6, -6.7 and 23.2%, respectively; and fasting triglyceride, -4.8, -27.1 and 93.0%, respectively. The 95% confidence intervals for the difference estimates in fasting LDL-cholesterol and fasting triglyceride concentrations all excluded zero, demonstrating superior lipid profiles with atazanavir plus saquinavir (P < 0.05 and P < 0.001, respectively). At 48 weeks, mean increases in high-density lipoprotein (HDL) cholesterol concentrations were comparable across the treatment regimens.
Figure 3 indicates the proportion of subjects with total cholesterol concentrations defined as desirable, borderline-high, or high based on National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines. Desirable and borderline-high total cholesterol concentrations (< 240 mg/dl) were reported in 94 and 82% of subjects in the atazanavir 400-mg and 600-mg groups, respectively, at baseline, and in 95 and 100% of subjects in the atazanavir 400-mg and 600-mg groups, respectively, at 48 weeks. In contrast, desirable and borderline-high total cholesterol concentrations were reported in 87% of subjects in the ritonavir group at baseline but in only 64% of ritonavir subjects at 48 weeks (P < 0.04 for both comparisons of atazanavir/saquinavir to ritonavir/saquinavir at week 48). The incidence of fasting hypoglycemia or hyperglycemia was infrequent and comparable across regimens (data not shown).
This randomized pilot study evaluated the safety, tolerability and efficacy of once-daily atazanavir plus saquinavir, as compared with twice-daily ritonavir plus saquinavir, both in combination with two NRTIs to which phenotypic sensitivity had been demonstrated in subjects who had experienced virological failure on a regimen that included a PI or an NNRTI. The rationale for using atazanavir with saquinavir was that the two drugs had non-overlapping resistance profiles and a favorable pharmacokinetic interaction that supported the once-daily dosing of saquinavir.
The HIV-1 RNA responses at 48 weeks demonstrated that once-daily atazanavir (400 or 600 mg) in combination with saquinavir had comparable virological efficacy to ritonavir plus saquinavir. Discontinuation for treatment-related adverse events, however, was approximately half as likely in the atazanavir groups as in the ritonavir group. At baseline, the somewhat higher mean baseline plasma HIV-1 RNA concentrations in the atazanavir groups, and the higher proportion of subjects with prior AIDS-defining diagnoses, may have favored the ritonavir group. The high incidence of treatment discontinuation in the ritonavir group, however, resulted in fewer subjects remaining in the study at 48 weeks, making interpretation of the results of ritonavir treatment difficult. This study did not detect significant differences in virological efficacy between these groups, but the relatively small sample size may not have allowed such differences to be demonstrated. Preliminary assessment of subjects with >= 1 baseline NEM or associated mutations, or >= 4 PI or associated mutations, showed that virological response was comparable across treatment groups. Because of the small number of subjects in this pilot study, conclusions about the comparative efficacy of the regimens in these subject populations should not be made.
The population enrolled in the present trial was similar to that included in prior studies of ritonavir plus saquinavir in antiretroviral-experienced patients ; that is, 87% of subjects were PI-experienced and 96% had not previously received saquinavir or ritonavir. This profile would also predict a favorable response to ritonavir plus saquinavir [25,29].
Comparisons between different studies are limited by differences in prior PI experience, eligibility criteria, and virologic assessments. However, available data suggest that the efficacy of ritonavir plus saquinavir observed in the present study is consistent with that reported previously. Most published studies of ritonavir plus saquinavir for patients failing a PI regimen are non-comparative, with small sample sizes and relatively short follow-up . Tebas et al. reported on a cohort of 26 subjects who had failed 48-week nelfinavir treatment in phase II clinical trials and were switched to a combination of ritonavir plus saquinavir with stavudine and lamivudine after two consecutive HIV-1 RNA measurements exceeded 5000 copies/ml . Two subjects discontinued at 3 weeks, and the remaining 24 subjects had < 500 HIV-1 RNA copies/ml. This HIV suppression was sustained at 24 weeks in 17 (71%) of the subjects, with five having < 40 HIV-1 RNA copies/ml .
Differing adverse events were observed in the atazanavir and ritonavir groups, although the incidence of serious and non-serious adverse events was comparable and consistent with the published toxicity profiles and experience with ritonavir and saquinavir [11,14]. More subjects in the ritonavir group developed diarrhea and nausea, whereas jaundice and hyperbilirubinemia occurred only in the atazanavir groups. The incidence of jaundice among subjects receiving atazanavir in this study was comparable to that in other atazanavir studies [20,22,27]. Hyperbilirubinemia was reversible and predominantly unconjugated (indirect). Pre-clinical data suggest that this is due to inhibition of uridine diphosphate glucuronosyltransferase 1A1 , the mechanism for bilirubin elevations with indinavir treatment . This mechanism is similar to that described for the reversible elevations in bilirubin levels associated with Gilbert syndrome, which are of little clinical significance . Grade 3 to 4 elevations in AST and ALT were observed more frequently in the ritonavir group. In acute hepatocellular necrosis due to drug-induced hepatitis, hyperbilirubinemia is accompanied by significant elevations in AST and ALT levels . In the atazanavir groups, grade 3 to 4 bilirubin elevations were not associated with grade 3 to 4 transaminase elevations. This is consistent with a low risk of hepatotoxicity, since acute hepatocellular necrosis due to drug-induced hepatitis is accompanied by significant elevations in AST and ALT levels .
Saquinavir and ritonavir, among other HIV-1 PIs , may cause dyslipidemia [35–38]. It is therefore remarkable that subjects receiving atazanavir plus saquinavir experienced favorable changes in lipid profiles. Although the observed decreases in total cholesterol and LDL-cholesterol suggest that atazanavir may prevent saquinavir-induced hyperlipidemia, the present study was not designed to answer this question. The atazanavir-associated decreases in cholesterol levels contrasts with substantial increases in these lipid concentrations observed in the ritonavir group. The proportion of subjects in the atazanavir groups with NCEP ATP III–defined  desirable or only borderline-high total cholesterol values increased at 48 weeks compared with baseline, but the proportion decreased in the ritonavir group, as was seen with atazanavir antiretroviral-naive patients .
In summary, once-daily atazanavir plus saquinavir with two NRTIs was safe and well tolerated in antiretroviral-experienced patients. This combination demonstrated comparable virological and immunological efficacy and resulted in fewer treatment discontinuations, as compared with twice-daily ritonavir plus saquinavir. Small mean percentage changes from baseline in serum lipid levels in the atazanavir groups were not of clinical significance, compared with prompt, marked and sustained increases from baseline in the ritonavir group of a magnitude that suggests clinical relevance. The favorable effect of atazanavir plus saquinavir on plasma lipid profiles suggests that this combination may reduce the risk of future cardiovascular events in this population.
The authors are grateful to the many persons with HIV-1 infection who volunteered for this study. The following members of the Protocol AI424–009 Study Group recruited, enrolled, provided medical management for and/or collected data from study subjects: P. Dellamonica, N. Nasser, D. Peterson, F. Raffi, M. Sension, J. Juega, Y. Mouton, M. Wohlfeiler, S. Echevarria, C. Katlama, H. Jaeger, J. Furtado, J.-L. Pellegrin, S. Walmsley, C. Acceturi, C. L. Besch, J. Macleod, C. Alves, C. Farthing, A. Lazzarin, D. Nunes, G. Friedland, R. Esposito, D. Salmon, F. Mazzotta, M. Lederman, R. Ciammarughi, A. Rachlis, J. E. Mobley, R. H. Dretler, M. A. Johnson, T. Evans, I. Cassetti, and P. Piliero.
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Keywords:Copyright © 2003 Wolters Kluwer Health, Inc.
atazanavir; protease inhibitors; highly active antiretroviral therapy; metabolic changes; salvage therapy