HIV protease inhibitors (PI), in combination with reverse transcriptase inhibitors, have extended and improved the quality of life for individuals with HIV infection[1-5]. Despite these gains, complications have emerged with PI therapy. Each PI is associated with acute toxicity that can be dose limiting [6,7] and although new twice daily regimens may be feasible with nelfinavir and saquinavir[8,9], PI-containing regimens are generally complex and require strict adherence[10,11]. Any level of reduced adherence appears to reduce virologic response. Metabolic complications, abnormal fat redistribution, and the development of drug resistance are other potential drawbacks that face patients and providers undertaking long-term combination antiretroviral therapy[13-17]. In clinical practice, virologic success of therapy is not guaranteed. In one study, the proportion of patients with plasma HIV RNA < 400 copies/ml after 6 months was only 40%. Therefore, new antiretroviral options are needed for persons infected with HIV.
Amprenavir (Agenerase, 141W94, formerly VX-478) (APV) is a novel peptidomimetic inhibitor of HIV protease. APV is an effective inhibitor of HIV in vitro. The 50% inhibitory concentration (IC50) against laboratory and clinical HIV isolates, including zidovudine (ZDV)-resistant isolates, in cell lines as well as in peripheral blood mononuclear cells (PBMC) ranges from 0.007 to 0.394 μmol/l[19-22]. Based on single-dose and multiple-dose studies, APV has a terminal half-life of 6-8 h[19,23,24]. At 1200 mg twice daily, the trough (12 h) plasma drug concentration was greater than 10 times the IC50 for HIV-1IIIB grown in PBMC. Binding to plasma proteins, predominantly a1-acid glycoprotein, increases the IC50 by two- to fivefold[19,25-27]. As with other HIV PI drugs, APV is metabolized primarily by the cytochrome P450 enzyme system, specifically CYP3A4, [19,28,29], which can potentially give rise to several drug-drug interactions[30-34]. APV does not induce CYP3A4 or other enzyme systems but does inhibit the 3A4 enzymes to a similar degree as that exhibited by indinavir and nelfinavir. At recommended doses, ZDV (300 mg, twice daily) and lamivudine (3TC; 150 mg, twice daily) do not alter the pharmacokinetics of APV. APV produces a 31% increase in ZDV exposure (based on area-under-the-curve) but does not affect 3TC exposure. Preliminary findings from in vitro studies suggest that APV may have reduced effect on proposed molecular mechanisms affecting lipid metabolism (e.g., retinoid signaling, lipolysis, and lipogenesis)[36,37].
Laboratory and clinical studies suggest that APV induces a novel initial pathway in the emergence of resistant HIV variants, with I50V as the predominant primary mutation[21,38-40]. Additional mutations at residues 46, 47, 54, 84, and the gag cleavage site have been observed. In PI-naive patients, I50V may be associated with cross-resistance to ritonavir but not to other PI drugs. In PI-experienced patients, variants with high-level resistance to other PI and extensive mutations in the protease gene tend to have the greatest reduction in susceptibility to APV (over eightfold); however, such high-level PI resistance does not always preclude susceptibility to APV.
The present clinical study was designed to assess the safety, tolerability, and antiviral activity of various doses of APV used in combination with 3TC and ZDV, and to identify the optimal dose of APV for future combination studies.
Study population and design
This phase II, multicenter, randomized, partially blinded, parallel-group study (Glaxo Wellcome protocol PROAB2002) enrolled 84 HIV-infected subjects, 18 years of age or older, with CD4 cell counts ≥ 150 3 106 cells/l and plasma HIV RNA ≥ 10 000 copies/ml. Study entry criteria stipulated no prior treatment with 3TC or a protease inhibitor and no prior treatment with didanosine or zalcitabine for greater than 1 year. Subjects with malabsorption, acute opportunistic infections, or standard laboratory values outside of prespecified ranges were excluded. The study protocol was approved by either an independent Ethics Committee or the Institutional Review Board affiliated with each study site.
Subjects were randomized centrally, stratified by continent (USA versus Europe), into one of the following four treatment arms: APV 900 mg twice daily, APV 1050 mg twice daily, APV 1200 mg twice daily, or placebo twice daily. APV was open-label in the 900 mg and 1200 mg groups, and blinded in the two remaining groups. All subjects received both ZDV (300 mg) and 3TC (150 mg). All study drugs (APV, ZDV, 3TC) were administered on a twice daily dosing schedule. Prior antiretroviral medications were discontinued 14 days before study entry. The study design plan was to randomize 20 subjects to each treatment arm. After week 12, subjects randomized to the control (3TC/ZDV/ placebo) arm had APV 1050 mg twice daily substituted for placebo while retaining the blind for subjects until the end of the study.
Blood samples were collected prior to dosing, at day 1, day 4, week 1, 2, 3, 4, 6, and 8, and then every 4 weeks. Efficacy was evaluated by measurement of plasma HIV-1 RNA, using a quantitative HIV-1 RNA polymerase chain reaction assay (Amplicor HIV-1 Monitor, Roche Molecular Systems, Branchburg, NJ, USA) with a sensitivity of 400 copies/ml (standard assay: for samples collected after week 20) or with a sensitivity of 20 copies/ml (ultradirect assay: samples taken up to and including week 20). CD4 counts were measured by flow cytometry. Progression of HIV disease was evaluated as development of a new Centers for Disease Control and Prevention (CDC) category C event  or death.
Safety assessments, including medical history and vital signs, hematology, clinical chemistry, and urinalysis, and asssessment of clinical adverse experiences were made on a similar schedule. In addition, physical examination, ophthalmologic examination, electrocardiogram, and thyroid function tests were performed at specific timepoints. Adverse events occurring during the trial were evaluated by the investigator and graded according to the protocol toxicity scales.
Plasma HIV RNA values (copies/ml) were log10 transformed prior to analysis. It was anticipated that an enrollment of 20 subjects in each treatment arm would provide 90% power (5% significance level) to detect a 0.72 log10 difference in the mean log10 HIV RNA change from baseline between any treatment group at week 12. Analysis at week 12 compared the 900, 1050, and 1200 mg APV dose groups with the control group with respect to time-weighted average area-under-curve analysis minus the baseline (AAUCMB) analysis for log10 HIV RNA using a two-tailed van Elteren‚s test on the actual values adjusting for continent (Europe and North America). AAUCMB values were also calculated for CD4 cell counts. AUC values of plasma HIV RNA and CD4 cells were calculated by the trapezoidal rule. A secondary analysis compared the 900, 1050, and 1200 mg APV dose groups with each other with respect to AAUCMB for log10 HIV RNA at week 12 using a two-tailed van Elteren‚s test on the actual values adjusting for continent. A similar analysis was performed for CD4 cell counts.
At weeks 48 and 60, analyses of the proportion of subjects with plasma HIV RNA below assay detection limits (< 400 copies/ml) were conducted on an as-treated basis (i.e., only subjects remaining on randomized therapy were included) and on a strict intent-to-treat basis (i.e., all randomized subjects were included and missing data and failures after week 8 were accounted for and carried forward as treatment failure).
Differences between APV and placebo with regard to adverse events were analyzed using a two-sided Fisher‚s exact test. Trends across the APV groups were analyzed using an exact two-sided Cochran-Armitage trend test. Median changes from baseline in laboratory values were compared between the APV and control groups using a two-sided Wilcoxon rank-sum test. The aforementioned analyses were done on a post-hoc basis, with P values being calculated only for the largest differences observed between groups.
Safety analyses included all subjects who were exposed to at least one dose of study treatment.
A total of 84 HIV-1-infected subjects were enrolled into the study at nine study sites in the United States and Europe. At baseline, the overall median CD4 cell count was 403 3 106 cells/l (range 31-901) and median plasma HIV RNA was 4.8 log10 copies/ml (range 2.5-6.2). The treatment groups were comparable with regard to demographics and baseline characteristics (Table 1), with the exception of a higher proportion of subjects with prior antiretroviral therapy in the 900 mg and 1050 mg groups and lower CD4 cell count in the 1050 mg group.
Of the 84 subjects randomized in the study, 80 received study medication (20 subjects in each treatment group). A total of 70 subjects (83%) completed the placebo-controlled phase of the study (week 0-7) without discontinuation of dosing (Table 2). Eight of 10 discontinuations were owing to adverse events and are described below.
Throughout the entire study period (week 0-60), 15 subjects permanently discontinued study drugs owing to adverse events considered possibly related to treatment (including one subject who discontinued placebo). Forty-two subjects (53%) were exposed to APV for more than 60 weeks. The median duration of APV exposure for all subjects was 427 days (range 5-553 days).
Plasma HIV RNA
All APV dosage groups had a median viral load reduction from baseline of greater than 1.6 log10 copies/ml at 12 weeks [intent-to-treat (Fig. 1a) and as-treated analyses]. At week 12, the 900 mg, 1050 mg, and 1200 mg APV groups had median decreases of 1.6, 1.8, and 1.9 log10 copies/ml, respectively, compared with a median decrease of 1.3 log10 copies/ml for the control group. The 1200 mg APV group maintained a median viral load reduction of approximately 2 log10 copies/ml through 60 weeks (range of median values: 1.9-2.6 log10 copies/ml).
Statistical comparison of each APV treatment group with the control group during the blinded portion of the study (up to week 12), using the AAUCMB, failed to show any significant difference (P = 0.170, 0.098, and 0.401, respectively, for the 900, 1050, and 1200 mg dose groups versus control). Comparisons among APV dosage groups did not show significant differences at 12 weeks (P > 0.5) or 24 weeks (P > 0.1).
The proportion of subjects by treatment group with plasma HIV RNA levels < 400 copies/ml is shown in Fig. 1b in an as-treated analysis and in Fig. 1c as an intent-to-treat analysis. In the as-treated analysis, the proportion of subjects with plasma HIV RNA < 400 copies/ml was above 80% for the 1200 mg APV dosage group after week 36. At weeks 48 and 60, the 1200 mg APV group had the greatest proportion of subjects with plasma HIV RNA < 400 copies/ml: 89% and 86%, respectively. Over the entire study period, the greatest difference in proportions between treatment groups was seen at week 12, when 28% of control subjects versus 60-70% of APV groups had undetectable values (< 400 copies/ml). In a strict intent-to-treat analysis, where missing values were considered treatment failures, the proportions at week 60 were lower: 25, 43, and 20% in the 900, 1050, and 1200 mg dose groups, respectively (Fig. 1c). At week 60, of the 64 subjects who were originally randomized to receive APV (intent-to-treat population), only 32 subjects remained on APV as a result of premature treatment discontinuation (as-treated population). Therefore, the intent-to-treat analysis may underestimate the efficacy of therapy since a large number of values were imputed as failures.
Analysis of plasma HIV RNA to a sensitivity of < 20 copies/ml was performed on samples collected to week 20. The median viral load reductions from baseline for all APV dosage groups were at least 2.4 log10 copies/ml by week 8 and ranged from 2.6 to 3.2 log10 copies/ml by week 20, as measured by the ultradirect assay. By as-treated analysis, 36, 39, and 33% of subjects in the 900, 1050, and 1200 mg groups had plasma HIV RNA levels < 20 copies/ml, respectively, at week 20 (24, 32, and 19% by intent-to-treat analysis).
CD4 cell counts
No statistically significant difference in the AAUCMB over the first 12 weeks was found between the control and APV groups or among the three APV dose groups.
Over the course of 60 weeks, an overall increase from baseline was noted in the median CD4 cell count in all four groups (Fig. 2). Intent-to-treat analysis at week 12 showed a median increase from baseline in CD4 cells of at least 83 3 106 cells/l across all four treatment groups. A median increase of at least 70 3 106 cells/l was maintained through week 60 for all groups, with the three groups who received APV throughout the study demonstrating the largest median increases at week 60.
As-treated analysis revealed a median increase of 175-216 3 106 cells/l at week 60 for the three groups who received APV throughout the study (data not shown). The greatest median increase in CD4 cells was observed in the 1200 mg APV group (216 3 106 cells/l).
During the first 12 weeks of the study, no notable differences in the incidence of adverse events, with the exception of rash and gaseous symptoms, were observed: 27% (16/60) of APV-treated subjects reported rash versus 10% (2/20) of control subjects (P = 0.215 by posthoc comparison); gaseous symptoms were more commonly reported in the control group: 50% (10/20) versus 18% (11/60) for APV-treated subjects (P = 0.009 by posthoc comparison). Other common adverse events occurred at a similar frequency in all four treatment groups during the first 12 weeks of therapy (data not shown).
The most common adverse events considered possibly related to treatment for the entire study are presented in Table 3. Subjects originally randomized to receive APV placebo (control group) received APV at 1050 mg twice daily after 12 weeks and are included in the APV 1050 mg group. The most frequent adverse events were nausea, diarrhea, fatigue, oral/perioral paresthesiae, and rash. Most of the adverse events were of mild or moderate intensity (grade 1 or 2). Only 5.3% of drug-related adverse events were grade 3 or 4. Although nausea occurred in 46% of subjects, it was usually of mild intensity, and only 3% (2/79) of subjects discontinued the study owing to this adverse event.
The occurrence of drug-related rash was greater with higher APV doses. Incidences of 5, 15, and 45% were noted for 900, 1050, and 1200 mg APV doses, respectively (P = 0.003 by posthoc comparison). The median time to onset of drug-related rash was 9.5 days (range 7-40 days). Rash led to treatment discontinuation in four subjects in the 1200 mg APV group (including one patient with Stevens-Johnson syndrome) and in one subject in the 900 mg APV group. Treatment discontinuation was not necessary for all rashes that occurred during APV therapy. Of 27 subjects who developed rash (regardless of assessment of causality), 14 subjects (52%) continued treatment in spite of the rash, while eight (30%) temporarily discontinued APV and were able to re-initiate therapy without rash recurrence.
Nine additional subjects discontinued APV because of other drug-related adverse events: mild diarrhea; moderate nausea, anemia, or allergic reaction; and severe nausea, abdominal pain, hyperglycemia, alanine aminotransferase and aspartate aminotransferase elevations, and triglyceride elevation. A statistical difference was noted among the three APV dosage groups in the proportion of subjects who discontinued APV because of the development of an adverse event considered possibly related to treatment: 10, 10, and 40% for the 900, 1050, and 1200 mg groups, respectively (P = 0.022 by posthoc comparison).
Eight subjects reported nine serious adverse events that were considered drug related by the investigator: two subjects in the control group and three each in the 900 mg and 1200 mg APV dosage groups. These were neutropenia (one) in the control group; anemia (one), rash (one), and elevated triglycerides (two events in one subject) in the 900 mg group; anemia (one) in the 1050 mg group; and rash (two) and the Stevens-Johnson syndrome (one) in the 1200 mg group. No deaths occurred during the study.
Grade 3 and 4 laboratory abnormalities are listed in Table 4. There was no evidence of an increase in laboratory abnormalities with APV dose. Fasting glucose, cholesterol, and triglyceride levels were not obtained. Two subjects, both of whom had abnormal (grade 1 or 2) baseline values, had glucose values > 250 mg/dl during the study. Only one subject had a triglyceride value > 1200 mg/dl. Triglyceride values increased by a median of 3 mg/dl for APV-treated subjects at week 12 and declined by 6 mg/dl in the control group. The difference between the two groups in median change from baseline in triglycerides levels was not statistically significant (P = 0.383). No grade 3 or 4 cholesterol values were noted and all cholesterol values remained within the normal range during the study. However, cholesterol increased by a median of 28 mg/dl in the APV dosage groups at week 12 compared with 2 mg/dl in the control group (P < 0.001), the clinical significance of which is unknown.
APV 1200 mg twice daily in combination with ZDV and 3TC provided potent and prolonged suppression of plasma HIV RNA in PI- and 3TC-naive subjects with CD4 counts ≥ 150 3 106 cells/l. By the as-treated analysis, at least 79% of subjects in the two highest APV dosage groups had plasma HIV RNA values < 400 copies/ml at weeks 48 and 60. In addition, the as-treated analysis showed that 89 and 86% of subjects receiving 1200 mg APV had < 400 copies/ml HIV RNA at week 48 and week 60, respectively, and a median CD4 count increase of 216 3 106 cells/l at week 60. By comparison, the intent-to-treat analysis showed that the proportion of subjects with HIV RNA < 400 copies/ml was lower (20% for the 1200 mg group at week 60). This difference between analyses was a consequence of treatment discontinuations (especially in the 1200 mg group) or missing values, which were counted as failures in the intent-to-treat analysis and may underestimate the treatment effect. The small sample size of this trial did not allow for firm statistical conclusions, although as-treated analysis suggests that the 1200 mg APV dose was marginally better than the 900 mg or 1050 mg doses (86, 64, and 79%, respectively, with viral load < 400 copies/ml at week 60). These findings support further exploration of the use of APV, in combination with ZDV and 3TC, as a new therapeutic option for antiretroviral-naive or minimally experienced individuals. Larger confirmatory studies are underway.
Although this study did not directly compare APV/3TC/ZDV combination therapy with other potent combination regimens, the APV-containing regimen represents an acceptable alternative for initial therapy in PI-naive patients. Other potent regimens containing nelfinavir, indinavir, ritonavir, saquinavir, or efavirenz should be expected to result in undetectable levels of HIV RNA (< 400 copies/ml) in a majority of individuals[6,43-45]. Until the results of randomized, comparative studies are available, considerations such as frequency of dosing, toxicity profile, and development of cross-resistance should be considered in determining treatment strategies.
This study demonstrated that treatment with APV can be safely given to HIV-infected subjects for prolonged periods. Nausea and rash were two of the more common adverse events in this study. Although nausea occurred in 46% of subjects, it was usually mild. There was no difference in occurrence of nausea between APV/3TC/ZDV groups and the control group in the initial 12 weeks of the study, and treatment was discontinued in only 3% of subjects because of this adverse event. The incidence of rash (45% in the 1200 mg APV group) was higher than that reported in subsequent phase III studies with APV dosed at 1200 mg twice daily: 28% in 659 subjects from several studies. No satisfactory explanation, other than small sample size, can be offered for the high incidence of rash observed in the present study. However, it is noteworthy that in the present study only 6% (5/79) of subjects discontinued APV because of rash and the majority of subjects were successfully ‚treated through‚ the event or had therapy re-initiated without recurrence of the rash. In subsequent studies, discontinuation of APV was only recommended when rash was accompanied with mucosal involvement, or allergic or systemic symptoms.
Preliminary clinical trial findings from another study have shown that 80% of subjects who failed APV monotherapy or 3TC/ZDV combination therapy responded to salvage therapy with indinavir/nevirapine/stavudine/3TC (plasma HIV RNA < 400 copies/ml at 24 weeks). These subjects had received APV for a short duration prior to the treatment switch. These data are intriguing, but the final results of prospective, controlled studies are needed to evaluate the potential for development of cross- resistance between APV and the other PI drugs.
APV has a longer half-life than the PI drugs currently approved and, therefore, can be given twice daily with confidence that the trough plasma concentration remains ten times the IC50 of most viral strains[19,23,24]. The dose flexibility of APV and the ability to dose without regard to food should facilitate a high level of medication adherence, which has been shown by several groups to be critical to success of antiretroviral therapy[10-12].
In summary, this 60-week study demonstrated that APV, in combination with 3TC/ZDV, can successfully achieve prolonged virologic suppression and improve CD4 cell counts in PI- and 3TC-naive individuals. Overall, the safety profile of the three APV dosage groups was comparable, with no significant differences in the incidence of adverse events among groups except for rash. The highest APV dose evaluated, 1200 mg, appeared to contribute to the higher proportion of subjects who maintained plasma HIV RNA < 400 copies/ml for extended periods (60 weeks). The overall risk/benefit evaluation supports the selection of the 1200 mg twice daily dose of amprenavir for further investigations in various antiretroviral combinations, for both initial therapy and for salvage therapy in other HIV-infected patient populations.
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The authors gratefully acknowledge the work and expertise of the Amprenavir PROAB2002 Study Team: Linda Meixner, RN, at University of California, San Diego, California, USA; Paul Couey and Timothy J. Enstrom at the AIDS Research Consortium of Atlanta, Atlanta, Georgia, USA; Beverly Putnam, RN, A. N. P. at University of Health Sciences, Denver, Colorado, USA; Bridget Wagner at ViRx Inc., San Francisco, California; Caroline Lascoux, MD, Geraldine Bayol, MD, and Olivier Taulera, MD at Hôpital Saint-Louis, Paris, France; D. van der Meijden, MD at University Hospital Rotterdam, Rotterdam, The Netherlands; Stephane de Wit, MD and K. Kabeya, MD at Saint-Pierre University Hospital, Brussels, Belgium; and the Glaxo Wellcome team Barbara McGarry and Kamlesh Patel (for data management), Leo Nacci (for statistical analysis), Richard Meyers (for analysis of plasma samples using ultradirect assay), and Judith Millard and Jane Yeo (for conduct of the trial and guidance).