A significant proportion of HIV-infected patients now seeking to initiate highly active antiretroviral therapy (HAART) have reached an advanced stage of disease [1,2, J.Gill, Seventh International Workshop on HIV Observational Databases, Italy, March 2003]. In order to offer this population optimal treatment options, new effective protease inhibitors (PIs) with flexible dosing options are needed.
Fosamprenavir (GW433908, FPV) is a PI for the treatment of HIV-infection in adults [3–6]. It is rapidly hydrolyzed to its active moiety amprenavir (APV) plus inorganic phosphate upon absorption and can be taken without food or water restrictions. Pharmacokinetic studies showed that co-administration of 1400 mg FPV once-daily (QD) with 200 mg ritonavir (RTV) QD or 700 mg FPV twice-daily (BID) with 100 mg RTV BID led to pharmacoenhancement with elevation of the plasma APV area under the curve (AUC) by approximately two-fold and plasma trough concentration (Cτ,ss: the concentration at the end of a dosing interval, τ, at steady state) by four- to six-fold in comparison with other studies of FPV in the absence of RTV [3,6]. The plasma APV trough concentrations achieved in these studies  exceeded the previously determined concentration required to inhibit by 50% the replication of wild-type virus  and facilitate once-daily dosing which may improve adherence and durability of response.
In this study, we compared the safety and antiviral efficacy of a FPV/ritonavir (FPV/r) QD regimen with nelfinavir (NFV) administered BID, both in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC) and lamivudine (3TC) delivered BID in antiretroviral therapy (ART)-naive adults. The primary objective was to compare the magnitude and durability of the antiviral response over 48 weeks. Secondary objectives were to compare the safety and tolerability of FPV/r QD and NFV BID, and to compare the virological, immunological, and metabolic responses to these regimens.
This study recruited ART-naive HIV-1-infected adults with plasma HIV-1 RNA (vRNA) ≥ 1000 copies/ml. Therapy-naive status was defined as < 4 weeks of therapy with any NRTI and no prior therapy with any non-nucleoside reverse transcriptase inhibitor (NNRTI) or PI. Patients were excluded if they had medical conditions that could have compromised their safety or interfered with drug absorption, required excluded medications, or had protocol-specified abnormal laboratory values. There were no exclusion criteria based on CD4+ cell counts or HIV disease classification .
This randomized, open-label study was conducted at 101 centers in North America, Europe, South Africa and Australia. The primary endpoint was the proportion of patients with vRNA < 400 copies/ml at week 48. Secondary endpoints included the proportion of patients with vRNA < 50 copies/ml at week 48, discontinuations of randomized PI due to adverse events, changes from baseline in vRNA, CD4+ cell counts, viral resistance, metabolic abnormalities and pharmacokinetics.
Patients were randomized to receive either FPV (GlaxoSmithKline, Ware, Hertfordshire, UK) 1400 mg QD (two 700 mg tablets) plus RTV (Abbott Laboratories, North Chicago, Illinois, USA) 200 mg QD (two 100 mg capsules), or NFV (Pfizer Pharmaceuticals, New York, USA) 1250 mg BID (five 250 mg tablets). Both treatments were administered with ABC and 3TC (GlaxoSmithKline) BID. Patients were stratified according to screening vRNA: ≥ 1000–10 000, > 10 000–100 000 and > 100 000 copies/ml.
Efficacy and safety assessments
At each visit, patients were assessed for HIV-associated conditions, CD4+ cell counts, and plasma HIV-1 RNA using the Roche Amplicor HIV-1 Monitor test version 1.5 (Roche Diagnostics, Basel, Switzerland) [ultrasensitive assay lower limit of detection (LLOD) = 50 copies/ml, upper limit of detection (ULOD) = 75 000 copies/ml; standard assay LLOD = 400 copies/ml, ULOD = 750 000 copies/ml]. Samples with HIV-1 RNA > 75 000 copies/ml using the ultrasensitive assay were re-tested using the standard assay.
Adverse events (AEs) were recorded throughout the study. Abnormal laboratory findings or other abnormal assessments the investigator judged to be clinically significant were recorded as AEs. Drug-related events were reported as related to the entire study drug regimen (PI plus NRTI).
In addition to standard clinical chemistry assessments throughout the study, fasting triglycerides, glucose, total cholesterol and high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol were assessed at day 1 and at weeks 8, 16, 24, and 48.
Treatment adherence was assessed by a self-reported Patient Medication Adherence Questionnaire, administered to 268 patients in five English-speaking countries. The questionnaire recorded adherence behavior for each study medication during each of the last 3 days and the weekend prior to weeks 1, 12, 24, and 48. Subjects who reported no missed doses received a ‘perfect’ adherence score.
Pharmacokinetic and phenotypic drug-susceptibility assessments
At selected centers, patients receiving FPV/r QD underwent Cτ,ss pharmacokinetic sampling at weeks 4, 8, and 12 to assess steady-state plasma APV concentrations .
The phenotypic drug-susceptibility (IC50) of virus isolated from these same patients at baseline was determined by ViroLogic Inc. (South San Francisco, California, USA) using the PhenoSense assay. 
The planned sample size of 624 patients provided approximately 85% power at the 2.5% significance level to detect differences in proportions of patients achieving vRNA < 400 copies/ml at week 48, using a 12% margin to assess non-inferiority.
For the primary endpoint, the two-sided 95% confidence interval (CI) around the difference in proportions between the FPV/r QD and the NFV BID groups was calculated. If the lower limit of the 95% CI lay above −12%, the non-inferiority of FPV/r QD to NFV BID would be established, whereas if it lay above 0, this would imply superiority of FPV/r QD to NFV BID. The confidence interval was stratified to reflect the vRNA randomization strata using Mantel–Haenszel weights. To provide a fuller description of the variability around the differences in proportions of virological and non-virological failures (the two sub-components of the primary endpoint), descriptive 95% CIs were calculated using the same method as above.
The intent-to-treat (ITT) population included all patients who received at least one dose of randomized treatment. The primary strategy for analyses of proportion endpoints was ITT rebound/discontinuation = failure (RD = F) where positive responders were those patients with confirmed vRNA levels < 400 copies/ml. Treatment failures comprised those patients whose vRNA remained ≥ 400 copies/ml, had a confirmed vRNA rebound to > 400 copies/ml irrespective of subsequent viral suppression, or discontinued the study for any reason. Patients with missing values were considered to have vRNA ≥ 400 copies/ml if the patient had vRNA ≥ 400 copies/ml on the previous or subsequent visit. The primary endpoint was also analyzed using an ITT missing/discontinuation = failure (M = F) approach where treatment failures comprised patients who had vRNA ≥ 400 copies/ml on one or more occasions, premature discontinuations for any reason, or who had missing data regardless of values on previous and subsequent visits. For both ITT analyses, patients who switched background NRTIs for reasons of intolerance were not considered treatment failures. The per protocol analysis included data collected while on randomized PI and excluded data following major protocol deviations.
The safety population consisted of all patients who received at least one dose of randomized treatment. Fisher's exact tests were performed to compare AE incidence rates and generate P-values (P < 0.01 was considered significant). For fasting triglycerides, HDL, LDL total cholesterol, fasting glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, a Wilcoxon rank sum test was performed to compare the median change from baseline between the treatment groups at week 48 with P-values < 0.01 considered significant. In addition to analysis of lipid parameters by toxicity grade, median values and changes from baseline were assessed according to National Cholesterol Education Program (NCEP) lipid categories .
Plasma APV concentrations were considered troughs (Cτ,ss) if the plasma sample was collected within 20–28 h after the previous dose of FPV/r. Amprenavir Cτ,ss values for a patient were averaged and these individual values were used to produce the overall summary and Cτ,ss/IC50 ratios.
A total of 649 patients were randomized and received treatment: 322 in the FPV/r QD group and 327 in the NFV BID group. Baseline characteristics were similar between groups (Table 1). The study population was ethnically diverse and included a relatively high proportion of females (27%). Median vRNA levels (4.8 log10 copies/ml) were high and median CD4+ cell counts (170 × 106 cells/l) low. Of note, 20% of patients had CD4+ cell counts < 50 × 106 cells/l whereas 22% had a history of CDC Class C (AIDS) events.
At week 48, analysis of the proportions of patients achieving vRNA < 400 copies/ml showed the FPV/r QD group (69%) to be non-inferior to the NFV BID group (68%), with a stratified treatment difference (FPV/r QD minus NFV BID) of 1% (95% CI: −6%, 8%) (Fig. 1a, ITT RD = F). The ITT M = F analysis provided similar results: 68% of patients in the FPV/r QD group and 65% of patients in the NFV BID group had vRNA < 400 copies/ml at week 48 (stratified treatment difference 3%, 95% CI: −4%, 10%). Analysis of the per protocol population supported these observations: 95% of patients receiving FPV/r QD and 91% of patients receiving NFV BID had vRNA < 400 copies/ml at week 48, giving a stratified treatment difference of 4% (95% CI: 0%, 9%).
In each treatment group, similar proportions of patients had vRNA < 50 copies/ml at week 48 by ITT RD = F (Fig. 1a, FPV/r QD: 55%; NFV BID: 53%) and ITT M = F analyses (FPV/r QD: 56%; NFV BID: 52%). For the per protocol population, 78% of patients receiving FPV/r QD and 72% of NFV BID recipients had vRNA < 50 copies/ml at week 48.
More patients experienced virological failure in the NFV BID group (17%) than the FPV/r QD group (7%); a difference of 10% (95% CI: 5%, 15%) in favor of FPV/r QD; reasons for virological failure are summarized in Table 2 (ITT RD = F). Conversely, there were more non-virologic failures in the FPV/r QD group (24%) versus the NFV BID group (15%); a difference of 9% (95% CI: 3%, 15%) in favor of NFV; slightly more patients receiving FPV/r QD discontinued the study due to adverse events or withdrawn consent, lost to follow-up and other reasons.
Treatment response, assessed by vRNA strata at study entry, indicates similar efficacy between groups and across strata. However, a higher percentage of patients with entry vRNA > 500 000 copies/ml achieved vRNA < 400 copies/ml in the FPV/r QD group (73%) than in the NFV BID group (53%). In a sub-hoc analysis of response at week 48 by baseline CD4+ cell counts, FPV/r QD maintained antiviral activity amongst those who entered with CD4+ cell counts < 50 × 106 cells/l and ≥ 50 × 106 cells/l (73 and 68% respectively, Fig. 1b, ITT RD = F). However, in the NFV group, a reduced proportion achieved vRNA < 400 copies/ml amongst patients with a baseline CD4+ cell count of < 50 × 106 cells/l (51%) compared to those having ≥ 50 × 106 cells/l (72%).
CD4+ cell counts increased for both treatment groups through 48 weeks. The median change from baseline was 203 and 207 × 106 cells/l for the FPV/r QD and NFV BID groups, respectively.
The percentage of patients reporting perfect adherence for all study drugs and at each visit assessed was 78% in the FPV/r QD group and 67% in the NFV BID group. Perfect adherence rates were consistently higher in the FPV/r QD arm at week 24 (FPV/r QD: 86%; NFV BID: 80%) and week 48 (FPV/r QD: 90%; NFV BID: 84%), although statistical significance was not assessed.
Overall, 41% of patients receiving FPV/r QD and 39% receiving NFV BID experienced grade 2–4 AEs considered to be drug-related (Table 3). Diarrhea, the only AE to be statistically significantly different in incidence between treatment groups, was significantly more common in NFV recipients than FPV/r QD recipients (16 versus 9%, P = 0.008).
Although 41 subjects were classified as non-virological failures in Table 2 for premature discontinuation of study drug due to adverse events, the ITT RD = F efficacy analyses only considers the first reason for treatment failure. Overall, 44 subjects withdrew from the study due to an AE: 28 (9%) FPV/r recipients versus 16 (5%) NFV recipients. Adverse events that led to withdrawal from the study in at least 1% of subjects in either treatment group were: suspected ABC hypersensitivity (FPV/r QD n = 4;NFV BID n = 3), diarrhea (FPV/r QD n = 4: NFV BID n = 1) and nausea (FPV/r QD n = 4: NFV BID n = 1).
The overall incidence of patients discontinuing ABC for a suspected hypersensitivity reaction was the same in both treatment groups (FPV/r QD: 8%; NFV BID: 8%). Subjects who discontinued ABC for suspected hypersensitivity reactions were allowed to continue on study with their randomized PI and substitute another NRTI for ABC.
Incidences of treatment-emergent grade 3/4 clinical chemistry and hematology abnormalities were generally low and comparable between treatment groups, although the incidence of grade 3 elevations in triglycerides and serum lipase was slightly higher in the FPV/r QD group (Table 4). Serum lipase elevations were observed in both groups and were predominantly asymptomatic. Elevations in liver enzymes were more commonly observed in patients entering the study with evidence of co-infection with hepatitis B and/or C: grade 3/4 ALT increases were observed in 3% (FPV/r QD) and 4% (NFV BID) of subjects without co-infection compared with 24% co-infected with hepatitis B and/or C in both treatment groups.
A slightly greater but insignificant median increase from baseline in triglycerides was observed in the FPV/r QD group (baseline 116 mg/dl; change + 58 mg/dl) compared to the NFV BID group (baseline 130 mg/dl; change + 41 mg/dl). Median baseline cholesterol values were: total 162 and 158 mg/dl; LDL 96 and 94 mg/dl and HDL 37 and 36 mg/dl for the FPV/r QD and NFV BID arms, respectively. Although median increases in total, LDL and HDL cholesterol were observed in both groups, there was no appreciable change in the total/HDL cholesterol ratio during the course of the study in either treatment group (median 4.3 for FPV/r QD and 4.5 for NFV BID at baseline vs 4.8 in both groups at Week 48). All median fasting cholesterol levels at Week 48 remained below (total, LDL) or above (HDL) the recommended NCEP intervention guidelines.
The FPV/r QD regimen delivered a median plasma APV Cτ,ss of 1.43 μg/ml (n = 38; range: 0.44, 3.41 μg/ml). The median IC50 value unadjusted for protein binding for APV against HIV-1 was determined in 34 of these patients with plasma amprenavir Cτ,ss data and was 0.0054 μg/ml (interquartile range: 0.0036, 0.0069 μg/ml). Assuming protein binding of 90% for APV, the median protein-binding adjusted plasma APV Cτ,ss/IC50 value achieved in this study was 27.70 (interquartile range: 14.48, 49.06)
The long-term therapeutic success of HAART in HIV patients is dependent on several factors including adherence , the patient's immunological and virological status [13–15], drug concentrations [16,17], regimen tolerability, and risk of emergence of drug resistant virus in treatment failures [18,19].
Fosamprenavir/ritonavir QD is a promising treatment option facilitated by the pharmacoenhancement of APV exposure with low dose RTV [6,7]. This is the first randomized, 48-week comparison of the efficacy and tolerability of FPV/r QD with NFV BID in ART-naive patients. The NFV comparator was chosen on the basis of its well-characterized safety profile  and its position as the leading PI at the time of study design and initiation.
Patients treated in SOLO are consistent with the population of patients currently initiating HAART in clinical practice [1,2,21, J. Gill, personal comm.]. However, the low median baseline CD4+ cell counts observed in both arms of SOLO (166 and 177 × 106 cells/l) illustrate that this population was more immune-compromised than the populations in which atazanavir (ATV) and lopinavir/ritonavir were recently evaluated in comparison with efavirenz and NFV, respectively [22,23]. In these studies, median baseline CD4+ cell counts were 286 and 232 × 106 cells/l, respectively.
The virologic response achieved with FPV/r QD in this population was potent as well as durable as indicated by the proportions of patients achieving < 400 copies/ml and < 50 copies/ml, as well as the maintenance of this response through week 48. Similar efficacy was observed by ITT analysis between the FPV/r QD and NFV arms since the higher number of NFV virologic failures was counterbalanced by more non-virologic failures in subjects receiving FPV/r QD.
The antiviral response to FPV/r QD was maintained in patients entering the study with a severely compromised immune system (< 50 × 106 CD4+ cells/l) or with high viral loads (> 500 000 copies/ml). This was in contrast to the NFV recipients, in which subjects with these same baseline characteristics did not respond as well as subjects with higher CD4+ cell counts or lower viral loads. A similar finding was also noted in the ACTG 384 trial where among subjects who had high viral loads at screening (vRNA > 5.0 log10), those receiving efavirenz, zidovudine and lamivudine had a better response than those receiving nelfinavir plus the same background drugs .
The overall response to FPV/r QD compares favorably with those observed for other PI regimen. In AI424034, 70% of patients receiving 400 mg of atazanavir QD achieved vRNA levels of < 400 copies/ml and 32% achieved < 50 copies/ml after 48 weeks , although the accuracy of these study results has been questioned due to potential confounders relating to sample collection methods. When comparing the responses seen in SOLO with those observed in M98-863 in which 75 and 67% lopinavir/ritonavir recipients achieved < 400 copies/ml and < 50 copies/ml after 48 weeks respectively , it should be noted that this population had a higher median CD4+ cell count at entry (232 × 106 cells/l) than that observed in SOLO (170 × 106 cells/l).
Although cross study comparisons are not ideal, the range of efficacy reported in studies evaluating NFV plus dual NRTIs in therapy-naive individuals is notable. In contrast with SOLO where 68% of NFV recipients achieved vRNA < 400 copies/ml at 48 weeks, the proportion achieving this response was 55% in NFV511 [750 mg three times daily (TID)], 61 and 58% in NFV542 (1250 mg BID and 750 mg TID, respectively) , 63% in M98-863 (750 mg TID)  and 56% in AI424-007 (750 mg TID) at 48 weeks .
Clinically relevant differences between the treatment groups were observed with respect to the risk of resistance in the treatment failures [26,27] impacting future PI and NRTI treatment options. Consistent with observations from other studies of boosted PI regimen , no primary or secondary protease (PRO) mutations were selected in patients experiencing therapy failure on FPV/r QD compared to 50% of NFV recipients (P < 0.001) [27,28]. Equally important, significantly fewer patients experiencing therapy failure in the FPV/RTV QD group (13%) developed mutations associated with resistance to NRTIs compared to patients in the NFV group (57%, P < 0.001) Detailed information on the resistance profile of FPV/r are reported elsewhere .
As observed with other regimens , the higher (≥ 80%) rates of perfect self-reported adherence in the FPV/r QD group at weeks 24 and 48 were consistent with the lower rate of virologic failure, significantly less grade 2–4 drug-related diarrhea, absence of food restrictions, lower pill count, and QD dosing of FPV/r compared with NFV BID.
FPV/r QD was well tolerated, with most adverse events being mild or moderate in intensity, and only a small proportion of patients withdrew from the study due to AEs. The incidence of grade 2–4 drug-related diarrhea in the FPV/r QD group was significantly less than that observed in the NFV group, and lower than that recently reported with other boosted PIs .
It is not clear why there were slightly more discontinuations due to diarrhea in the FPV/r QD arm than the NFV arm. One explanation may be that physicians and patients were more aware of management of diarrhea as a side effect of NFV and thus drug discontinuation was seldom warranted whereas the lesser known safety profile of FPV/r led to more cautious management of diarrhea events.
Rashes not considered by investigators to be part of ABC hypersensitivity reaction were reported with low incidence in both arms. The incidence of suspected ABC hypersensitivity reaction reported in this study (8% in each group) is higher than the approximate 5% previously reported in clinical trials . This supports the fact that there is a heightened awareness to ABC hypersensitivity reaction and treating physicians are adopting an appropriately conservative approach to diagnosis .
The low incidences of grade 3/4 laboratory abnormalities compare favorably with incidences reported with other boosted PIs . In this population, generally comparable fasting lipid profiles were observed in both the FPV/r QD and NFV treatment groups. The slight elevation of triglyceride levels in the FPV/r QD group may possibly be attributed to use of ritonavir. Further lipid analyses have been presented elsewhere .
In conclusion, the results of this study in ART-naive, HIV-infected patients with high viral load and low CD4+ cell counts, demonstrate the potency, durability, and tolerability of the FPV/r QD regimen. No FPV/r QD recipients developed PRO mutations and significantly fewer recipients developed mutations in RT throughout the 48 weeks of treatment, hence, preserving future treatment options. Furthermore, the combination of fosamprenavir and ritonavir provides the benefits of no food restrictions, a low daily pill burden, once-daily dosing and a favorable lipid profile. Overall, these data support the use of FPV/r QD in a first line regimen or early in the treatment continuum.
We gratefully acknowledge the participation of all APV30002 (SOLO) patients, investigators and study co-ordinators. We thank Justin Cook and Lesley Kahl for manuscript editing and writing assistance.
Sponsorship: GlaxoSmithKline Research and Development supported this study.
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