Suppressing HIV replication while minimizing the adverse metabolic effects of treatment is difficult in patients who have experienced treatment failure [1–6]. Only one-third of patients with exposure to two drug classes achieve undetectable HIV-1 RNA concentrations with subsequent regimens . Regimens containing two HIV-1 protease inhibitors (PIs) with non-overlapping resistance profiles may increase drug bioavailability, possibly delaying or preventing the emergence of PI-resistant variants in these patients [8–10]. Ritonavir and saquinavir have non-overlapping resistance profiles ; when co-administered, ritonavir increases saquinavir plasma concentrations by inhibiting the 3A4 isoform of cytochrome P450 . Success of such dual PI regimens, however, is often limited by acute and chronic toxicities, including insulin resistance and hyperlipidemia, among others [5,12–16].
Atazanavir is a potent, safe and well-tolerated azapeptide HIV-1 PI [17,18]. Its in vitro 50% inhibitory concentration (IC50) is 2.6 to 5.3 nmol. Many HIV-1 variants resistant to one or two PIs remain sensitive to atazanavir in vitro . Conversely, atazanavir-resistant variants may remain sensitive to other PIs . The trough (Cmin) steady-state plasma concentration of atazanavir following an oral dose of at least 400 mg, taken with a light snack or meal, exceeds the concentration required to inhibit 50% of HIV-1 replication (EC50) for HIV-1 for greater than 36 h [20–24]. Its inhibitory quotient (IQ = Cmin/EC50) of 10.2 to 25.5 is among the highest of the current PIs without pharmacological boosting with ritonavir [19,25,26].
In 48-week studies involving antiretroviral-naive patients (protocols AI424-007 and AI424-008), once-daily atazanavir demonstrated comparable efficacy and safety to nelfinavir given two or three times daily, each with two nucleoside analogue reverse transcriptase inhibitors (NRTIs) . Diarrhea was more common with nelfinavir, and jaundice and hyperbilirubinemia were more common with atazanavir. Atazanavir was not associated with clinically relevant increases in total cholesterol, fasting low-density lipoprotein (LDL) cholesterol or fasting triglyceride concentrations . In contrast, patients receiving nelfinavir experienced prompt, marked and sustained elevations in these concentrations that could be of clinical significance. For the purpose of optimizing safety and maintaining antiviral efficacy, the 400-mg dose of atazanavir, given once daily, was chosen for evaluation in phase III trials.
The present 48-week pilot study compared the safety and efficacy of once-daily atazanavir (at two dose levels) plus saquinavir with twice-daily ritonavir plus saquinavir in antiretroviral-experienced adults, each with two NRTIs. Atazanavir and saquinavir have non-overlapping resistance profiles, and atazanavir markedly increases plasma saquinavir concentrations to allow once-daily dosing of both drugs (Colonno and Schnittman, BMS data on file).
The primary objective was to assess safety and tolerability of once-daily atazanavir at two dosage levels (400 and 600 mg), in comparison with twice-daily ritonavir (400 mg), each in combination with saquinavir. Secondary objectives were to compare virological and immunological responses between groups. The atazanavir 400-mg group received 400 mg atazanavir once daily plus 1200 mg saquinavir. The atazanavir 600-mg group received 600 mg atazanavir once daily plus 1200 mg saquinavir. The ritonavir group received 400 mg ritonavir twice-daily plus 400 mg saquinavir twice-daily. Subjects received two NRTIs to which phenotypic sensitivity had been demonstrated. Subjects were randomized in a 1 : 1 : 1 ratio based on a permuted block design stratified by clinical trials site. The study was blinded only to atazanavir dose level. All other study drugs were used open label. Saquinavir was administered in the 200 mg strength soft-gel capsule formulation (Fortovase; Roche Pharmaceuticals, Nutley, New Jersey, USA).
For each potential enrollee, phenotypic susceptibility testing was performed using the PhenoSense assay (ViroLogic Clinical Reference Laboratory, South San Francisco, California, USA), and results were provided to the site investigator before entry. Subjects were prescribed two NRTIs to which the screening viral isolate was susceptible (≤ 2.5 times the EC50). The NRTIs were selected by the provider based on these results. Allowable NRTI combinations were stavudine plus didanosine, stavudine plus lamivudine, zidovudine plus didanosine, or zidovudine plus lamivudine.
Safety assessments included serious adverse events, clinical adverse events, treatment discontinuations and dose modifications. Efficacy assessments included magnitude and durability of change from baseline to 48 weeks in plasma HIV-1 RNA levels, CD4 cell counts and the proportion of subjects achieving a virological response, defined as either a decrease of at least 1.0 log10 copies/ml in HIV-1 RNA copies/ml from baseline or an HIV-1 RNA level < 400 copies/ml at 48 weeks. Institutional review boards of participating institutions approved the study, and all subjects gave written informed consent.
Eligible subjects were antiretroviral-experienced adults at least 18 years of age, with plasma HIV-1 RNA of at least 1000 copies/ml (Amplicor, Roche Molecular Systems, Branchburg, New Jersey, USA) and a CD4 cell count of at least 100 × 106 cells/l (or 75 × 106 cells/l if no prior AIDS-defining illness) while receiving a PI- or non-nucleoside analogue reverse transcriptase inhibitor (NNRTI)-containing regimen for at least 24 weeks. A documented virological response to the prior regimen was required, defined as a decrease of at least 1.0 log10 HIV-1 RNA copies/ml, or < 400 HIV-1 RNA copies/ml (as assessed by the Amplicor HIV-1 Monitor version 1.0 and 1.5) or 500 copies/ml (as assessed by the Quantiplex HIV RNA bDNA assay; Chiron Diagnostics, Emeryville, California, USA). Phenotypic susceptibility, defined as an EC50 ≤ 2.5 times the control-strain EC50, was required to both agents in at least one of the four allowable NRTI combinations. Eligibility also required phenotypic susceptibility to atazanavir, ritonavir and saquinavir, defined as no more than 10 times the EC50 of the control strain.
Subjects were excluded if they had a newly diagnosed opportunistic infection or had undergone prior therapy with saquinavir or ritonavir for 30 or more days, with any NNRTI other than that in the current regimen or with more than two NRTIs. Breast-feeding, active alcohol or substance abuse, a history of acute or chronic pancreatitis, proven or suspected hepatitis, and grade 2 or greater peripheral neuropathy were additional exclusion criteria. Women were required to have a negative pregnancy test within 72 h of study medication initiation.
Subjects were evaluated at screening, baseline, weeks 4, 8, 12, and 16, and every 8 weeks up to 48 weeks. Plasma HIV-1 RNA levels were determined by AMPLICOR HIV-1 Monitor UltraSensitive assay and were augmented with data from AMPLICOR HIV-1 Monitor assay, versions 1.0 or 1.5 (Roche Molecular Systems), with limits of quantification of 50 and 400 copies/ml, respectively, on samples shipped at ambient temperature. Genotypic analyses were carried out by methods previously described .
Safety assessment included medical histories, physical examinations, laboratory evaluations and reports of adverse events, grouped using a modified version of the US Food and Drug Administration Coding Symbols for Thesaurus of Adverse Reaction Terms, version III (COSTART III).
Management of adverse events or intolerance
Toxicities were graded according to the modified World Health Organization criteria, scale of 1 to 4. Dose modification was permitted for toxicity. In subjects with grade 4 isolated hyperbilirubinemia [bilirubin levels 5 to 10 times the upper limit of normal (ULN)], atazanavir was withheld until repeat testing demonstrated grade 3 or less, when atazanavir was resumed at a dose reduced by 200 mg. Subjects with bilirubin elevations to greater than 10 times the ULN were discontinued. Subjects could request withdrawal from the study if they experienced major, serious and unexpected or life-threatening toxicity, pregnancy, need for a medication prohibited by the protocol or an increase in plasma HIV-1 RNA levels from a confirmed undetectable level to a detectable level.
Analyses were performed on all treated subjects (i.e, subjects who initiated treatment with a PI). HIV-1 RNA values outside the upper (or lower) limit of quantification were assigned a value of one more (or one less) than the limit. The proportions of subjects with virological response at 48 weeks were compared using normal approximations. This study was designed with a target sample size of 75 treated subjects (25 per treatment group) to assess safety and tolerability. This sample size provides 69% power to demonstrate in the principal efficacy analysis that the longitudinal virological suppression with any dose of atazanavir/saquinavir is similar to that with ritonavir/saquinavir. For the intent-to-treat: noncompleter equals failure analysis of virological response, the assay value for subjects who remained on treatment was classified as a virological response based on the HIV-1 RNA measurement closest to the scheduled visit and within a predefined window, with the denominator being the total number of randomized subjects. Subjects not meeting the virological response criteria, and subjects who discontinued the study prior to their scheduled visit, were classified as failures in this analysis. Subjects who remained on treatment but missed their 48-week visit were classified as responders only if their previous and subsequent measurements met the response criteria. Analysis of virological response based on observed data was also performed. The denominator excluded subjects who discontinued the study prior to their 48-week visit. Statistical analyses comparing the changes from baseline in CD4 cell count were not carried out.
Lipid concentrations were compared between atazanavir-treated subjects and ritonavir-treated subjects using mean percentage changes from baseline to 48 weeks based on t distributions. Discrete variables were compared using Fisher's exact test. All comparisons used a two-sided alpha level of 0.05.
A total of 85 subjects in North America, South America and Europe were randomized to the atazanavir 400-mg (n = 34), atazanavir 600-mg (n = 28) and ritonavir (n = 23) groups (Table 1). Three subjects (4%) did not initiate therapy with the study drug, two in the atazanavir 400-mg group and one in the atazanavir 600-mg group. Baseline demographics were comparable across groups (Table 2), although the proportion of subjects with prior AIDS-defining diagnoses was higher in the atazanavir 400-mg and 600-mg groups than in the ritonavir group (32, 25 and 13%, respectively). Mean baseline HIV-1 RNA levels were also higher in the atazanavir 400-mg and 600-mg groups than in the ritonavir group (4.50, 4.28 and 4.10 log10 copies/ml, respectively). The proportion of subjects with baseline HIV-1 RNA levels > 30 000 copies/ml was higher in the atazanavir 400-mg group than in the atazanavir 600-mg and ritonavir groups (53, 36 and 22%, respectively; P = 0.03 for atazanavir 400 mg versus ritonavir). Mean baseline CD4 cell count for all subjects was comparable across treatment groups (333 × 106 cells/l). The median duration of prior PI therapy was approximately 2 years, and was comparable across groups.
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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