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SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients
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AIDS: Volume 18(11) 23 July 2004
Gathe, Joseph C Jra; Ive, Prudenceb; Wood, Robinc; Schürmann, Dirkd; Bellos, Nicholaos Ce; DeJesus, Edwinf; Gladysz, Andrzejg; Garris, Cindyh; Yeo, Janej
From the aTherapeutic Concepts, P.A., Houston, Texas, USA, the bClinical HIV Research Unit, Parktown, the cDepartment of Medicine, University of Cape Town, Republic of South Africa, the dCharité University Hospital, Campus Virchow-Klinikum, Department of Infectious Diseases, Berlin, Germany, the eSouthwest Infectious Disease Associates, Dallas, Texas, the fIDC Research Initiative, Altamonte Springs, Florida, USA, the gWroclaw University School of Medicine, Department and Clinic of Infectious Diseases, Wroclaw, Poland and Clinical Development and Medical Affairs, HIV, GlaxoSmithKline, hResearch Triangle Park, North Carolina, USA and jMiddlesex, UK.
The authors concluded: "...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..."
Pill count: 2 tabs FPV ("908") daily plus 2 RTV caps daily.
ABSTRACT
Objective: To compare the magnitude and durability of the antiviral response to fosamprenavir (FPV) plus ritonavir (RTV) once-daily (FPV/r QD) with nelfinavir twice-daily (NFV BID), each administered with abacavir and lamivudine twice-daily.
Methods: An international, phase III, randomized, open-label study in antiretroviral therapy-naive, HIV-infected adults.
Patients were randomized to receive either FPV 1400 mg QD (two 700 mg tablets) plus RTV 200 mg QD (two 100 mg capsules), or NFV 1250 mg BID (five 250 mg tablets). Both treatments were administered with ABC and 3TC BID. Patients were stratified according to screening vRNA: >= 1000-10 000, > 10 000-100 000 and > 100 000 copies/ml.
Results: Patients with advanced HIV disease received FPV/r QD (n = 322) or NFV BID (n = 327).
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. Of note, 20% of patients had CD4+ cell counts < 50, whereas 22% had a history of CDC Class C (AIDS) events.
At week 48, 69% of patients in the FPV/r QD group and 68% in the NFV BID group had plasma HIV-1 RNA (vRNA) < 400 copies/ml, whereas 55% of patients in the FPV/r QD group and 53% in the NFV BID group had vRNA < 50 copies/ml (intent to treat, rebound/discontinuation = failure). 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.
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%) 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%).
More patients in the NFV BID group (17%) experienced virological failure than in the FPV/r QD group (7%). Efficacy of FPV/r QD was maintained in patients with CD4+ cell counts < 50 cells/l or vRNA >= 100 000 copies/ml at entry. At week 48, median CD4+ cell counts were increased to 203 cells/l (FPV/r QD group) and 207 cells/l (NFV BID group).
There were 23 NFV premature discontinuations as per protocol switch vs 1 for FPV/r. 6 never achieved viral load <400 in NFV vs 1 for FPV/r. Non-vrologic failure (premature discontinuation) was 24% for FPV/r vs 15% for NFV.
Although 41 subjects were classified as non-virological failures 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).
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 cells/l and >= 50 cells/l (73 and 68% respectively, 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 cells/l (51%) compared to those having >= 50 cells (72%).
At the Bangkok IAC GSK reported a post-hoc analysis of viral response in patients with high VL and low CD4 count at study entry.
DEFINITIONS: Low CD4 <50 cells; high Cd4 >50; low VL < 100,000 c/ml; high VL >100,000 c/ml.
(I will note where there were differences between NFV & FPV/r responses)
Low CD4/low VL
<50 c/ml (RD=F): 48% NFV, 60% 908/r.
Low VL/High CD4
<400 c/ml (RD=F): 73% NFV; 68% FPV/r.
High VL/ Low CD4
<400 (RD=F): 74% 908/r, 44% NFV
<50 (RD=f): 51% FPV/r, 33% NFV
High VL/High CD4
<400 (RD=F): 67% 908/r, 71% NFV
There were no PI mutations among patients with viral failure taking FPV/r but 8-14% of patients receiving NFV & had viral failure had PI mutations except in the low VL/high CD4 group where 1% had PI mutations. There was a similar trend regarding nuke mutations: 0% in FPV/r viral failures except 6% in high VL, low CD4 group; 14-38% in NFV group, except it was 1% in lowVL/high CD4 group.
CD4+ cell counts increased for both treatment groups through 48 weeks. The median change from baseline was 203 and 207 cells/l for the FPV/r QD and NFV BID groups, respectively.
SAFETY ANALYSIS: Overall, 41% of patients receiving FPV/r QD and 39% receiving NFV BID experienced grade 2-4 AEs considered to be drug-related. Both regimens were generally well tolerated. Diarrhea was more common on NFV BID than on FPV/r QD (16 versus 9%; P = 0.008). Fasting lipid profile results were generally favorable in both treatment arms. FPV/r QD maintained plasma amprenavir (APV) trough concentrations above the mean phenotypic drug-susceptibility (IC50) for wild-type virus for APV.
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. 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.
Self-reported adherence
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.
Conclusion: As a first choice protease inhibitor with a low daily pill burden, FPV/r QD was well tolerated and provided potent, durable antiviral suppression.
Introduction
A significant proportion of HIV-infected patients now seeking to initiate highly active antiretroviral therapy (HAART) have reached an advanced stage of disease [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. 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 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.
AUTHOR DISCUSSION
The long-term therapeutic success of HAART in HIV patients is dependent on several factors including adherence, the patient's immunological and virological status, drug concentrations, regimen tolerability, and risk of emergence of drug resistant virus in treatment failures.
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 [20] 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. However, the low median baseline CD4+ cell counts observed in both arms of SOLO (166 and 177 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. In these studies, median baseline CD4+ cell counts were 286 and 232 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 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 cells/l) than that observed in SOLO (170 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) [23] 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 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). 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.
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