Antiviral Therapy 5: 215-225
Amprenavir in combination with lamivudine and
zidovudine versus lamivudine and zidovudine alone
in HIV-1-infected antiretroviral-naive adults
Jeffery C Goodgame1, John C Pottage Jr2*, Helmut Jablonowski3, W David Hardy4, Allan Stein5,
Margaret Fischl6, Patrick Morrow7, Judith Feinberg8, Cynthia Hanson Brothers9, Imogen Vafidis10,
Pantaleo Nacci10, Jane Yeo10 and Louise Pedneault9 for the Amprenavir PROAB3001 International
Study Team
1
Central Florida Research Initiative, Altamonte Springs, Fla., USA (currently with Pfizer, Ohio, USA)
Vertex Pharmaceuticals, Cambridge, Mass., USA
3
Universitatsklinik Dusseldorf, Medizinische Klinik & Poliklinik, Dusseldorf, Germany
4Pacific Oaks Research, Beverly Hills, Calif., USA
5Care Resource, Coral Gables, Fla., USA
6University of Miami, AIDS Clinical Trial Unit, Miami, Fla., USA
7ID Associates, Dallas, Tex., USA (Currently with Aesculapius Medical Health Group, Dallas, Tex., USA)
8University of Cincinnati, Holmes Division, Cincinnati, Ohio, USA
9Glaxo Wellcome, Research Triangle Park, N.C., USA
10Glaxo Wellcome, Greenford, UK
2
*Corresponding author: Tel: +1 617 577 6322; Fax: +1 617 577 6501; E-mail: pottage@vpharm.com
Objectives: To compare the antiviral activity and safety of
a new protease inhibitor, amprenavir (141W94) in combination with lamivudine and zidovudine, versus lamivudine
and zidovudine alone in HIV-1 infected, antiretroviralnaive subjects.
Design: Subjects (n=232) with a CD4 T cell count of ≥200
cells/mm3, plasma HIV-1 RNA levels of ≥10000 copies/ml,
and ≤4 weeks of prior nucleoside antiretroviral therapy,
were stratified according to baseline plasma HIV-1 RNA
level (10 000–30 000; 30 000–100 000; or >100 000
copies/ml). Subjects received double-blind treatment with
either 1200 mg amprenavir twice daily in combination
with lamivudine (150 mg twice daily) and zidovudine (300
mg twice daily) (amprenavir/lamivudine/zidovudine) or
matched placebo, lamivudine and zidovudine for 16 weeks.
Thereafter, subjects with confirmed plasma HIV-1 RNA
levels of ≥400 copies/ml could add open-label amprenavir
or switch to other antiretrovirals and continue treatment
for up to a minimum of 48 weeks. The primary endpoint of
the study was defined as the proportion of subjects with
plasma HIV-1 RNA of <400 copies/ml at 48 weeks.
Results: At 48 weeks, a significantly greater proportion of
amprenavir/lamivudine/zidovudine subjects had plasma
HIV-1 RNA levels <400 copies/ml than lamivudine/ zidovudine subjects in the overall population: 41 versus 3%
(intent-to-treat missing equals failure analysis) (P<0.001);
93 versus 42% (as-treated analysis) (P<0.001); and within
each of the three randomization strata (P<0.001). Subjects
on amprenavir/lamivudine/ zidovudine experienced longer
time to event (permanent discontinuation of randomized
therapy or viral rebound) than those on lamivudine/
zidovudine (median of 33 versus 13 weeks; P<0.001). A
significantly greater incidence of drug-related nausea,
vomiting, rash and oral/perioral paresthesia was observed
with amprenavir/lamivudine/zidovudine than with lamivudine/zidovudine.
Conclusions: Amprenavir, in combination with lamivudine
and zidovudine, has potent and durable antiviral activity in
antiretroviral-naive subjects over 48 weeks. Amprenavir
was safe and generally well tolerated.
Introduction
HIV-1 protease inhibitors in combination with other
antiretrovirals have been shown to achieve reduction in
the levels of plasma HIV-1 RNA to levels below the
detection limit of current assays [1–3]. In addition,
protease inhibitor (PI)-containing regimens including
indinavir, saquinavir, ritonavir or nelfinavir and two
nucleoside reverse transcriptase inhibitors (NRTIs),
©2000 International Medical Press 1359-6535/00/$17.00
such as zidovudine, lamivudine, didanosine,
zalcitabine or stavudine, have been shown to suppress
viral replication in lymphoid tissue [4–8]. Because
HIV-1 protease inhibitor-containing regimens have
demonstrated potent antiviral activity and a dramatic
reduction in HIV-related deaths and opportunistic
infections [9,10], most HIV/AIDS treatment guidelines
215
JC Goodgame et al.
[11–13] currently recommend the consideration of
HIV-1 PIs in the initial treatment of HIV-1 infection.
Amprenavir (141W94; Agenerase), which was structurally designed based on the 3D structure of the
protease enzyme, is a newly approved and potent
inhibitor of HIV-1 protease (Ki=0.6 nM) [14] and of
HIV-1 replication in vitro (mean IC50=29 nM against
216 HIV clinical isolates) [15]. Clinical data indicate
that amprenavir is well absorbed and can be administered with or without food, although it should not be
taken with a high-fat meal [16]. Twice-daily dosing is
feasible with amprenavir because of its long half-life of
between 7 and 10 h [16] compared with that of 1.8–5
h for currently marketed HIV-1 PIs [17]. Clinical trials
with amprenavir in combination with other antiretrovirals, such as abacavir, zidovudine, lamivudine,
indinavir, saquinavir and nelfinavir, are ongoing and
have demonstrated potent antiviral activity, as
evidenced by decreased plasma HIV-1 RNA levels and
increased CD4 counts [18–21]. Additionally, amprenavir is safe, with most adverse events being transient
and mild-to-moderate [19–22].
This study was designed to evaluate the efficacy and
safety of amprenavir in combination with lamivudine
and zidovudine versus lamivudine and zidovudine in
antiretroviral-naive subjects with CD4 counts of ≥200
cells/mm3, and to assess the durability of this effect
over 48 weeks of treatment. However, treatment modifications were encouraged from week 16 onwards in
subjects whose HIV-1 RNA levels were not maintained
at ≤400 copies/ml.
treatment, begin open-label amprenavir therapy, add
abacavir, add a commercially available HIV protease
inhibitor (except ritonavir), change NRTIs, or switch
to a commercially available PI (including ritonavir),
and continue study participation for up to a minimum
of 48 weeks (open-label phase). Subjects with HIV-1
RNA levels consistently below 400 copies/ml remained
on blinded, randomized study medication (randomized
phase).
Materials and Methods
Laboratory methods
Subjects and study design
Male or female adults (≥18 years) with a confirmed
diagnosis of HIV-1 infection gave informed consent to
participate in this randomized, placebo-controlled
study (PROAB3001) which was approved by the
Institutional Review Board/Ethics Committee at 23
clinical sites, 13 in the USA and 10 in Europe. Subjects
with CD4 counts of ≥200 cells/mm3, who were antiretroviral-naive (≤4 weeks previous NRTI treatment)
and CDC category A or B, were randomly assigned in
a double-blind manner to receive 1200 mg amprenavir
twice daily or matched placebo twice daily without
regard to food, in combination with lamivudine (150
mg twice daily) and zidovudine (300 mg twice daily)
for 16 weeks. Randomization was stratified according
to screening plasma HIV-1 RNA (10 000–30 000,
30 000–100 000 or >100 000 copies/ml). At week 16
and thereafter, subjects who met the protocol-defined
switch criterion (defined as two consecutive plasma
HIV-1 RNA values of ≥400 copies/ml measured within
3 weeks of one another), could remain on randomized
216
Measurements
Blood was collected at baseline, at weeks 1, 2, 4, 8, 12,
16 and every 4 weeks thereafter for analysis of plasma
HIV-1 RNA levels, absolute CD4 lymphocyte counts,
clinical chemistry and haematology evaluations. Blood
samples for most laboratory evaluations were not
collected in the fasting state because subjects were
required to fast overnight only for week 2 and 12 evaluations. Throughout the study period, clinical adverse
events and haematology or clinical chemistry laboratory abnormalities were assessed and graded according
to ACTG toxicity scales [23] wherever possible (grade
1 or mild, to grade 4 or very severe). Durability of the
plasma HIV-1 RNA response over 48 weeks was
measured as time-to-event. An event occurred when
any one of the following conditions was met:
confirmed plasma HIV-1 RNA levels ≥400 copies/ml,
permanent discontinuation of randomized therapy
(including confirmed plasma HIV-1 RNA level of ≥400
copies/ml), progression to a new confirmed CDC category C event or death.
A reverse transcriptase PCR assay (Amplicor HIV-1
Monitor, Roche Molecular Systems, Branchburg, N.J.,
USA) was used to measure plasma HIV-1 RNA
(Primers 1.0 Standard Assay, limit of detection = 400
copies/ml; Primers 1.0, Ultrasensitive Assay, limit of
detection = 50 copies/ml). CD4 lymphocyte counts
were determined using flow cytometry (FACScalibur,
Becton Dickinson Three-Color Flow Cytometry, San
Jose, Calif., USA). All efficacy and safety laboratory
measurements were performed at Covance Central
Laboratories (Geneva, Switzerland; and Indianapolis,
Ind., USA).
Statistical analyses
A sample size of 115 subjects per treatment group was
estimated to provide ≥85% power in detecting a 20%
difference between treatment groups at the primary
endpoint, which was the proportion of subjects with
plasma HIV-1 RNA levels of <400 copies/ml at week
48. P-values at or below the 0.05 alpha level were
considered significant.
Efficacy variables were analysed on an intent-to©2000 International Medical Press
Efficacy of amprenavir with lamivudine and zidovudine versus lamivudine and zidovudine alone
treat (ITT) basis (which includes data from all randomized subjects) and on an as-treated basis (which
includes data from all subjects who remained on
randomized treatment only). Two separate ITT
analyses were performed. The ITT missing equals
failure analysis, all premature discontinuations from
randomized therapy, new confirmed CDC category C
events, deaths and missing values were considered failures. To account for subjects who switched therapy but
did not experience virological failure during the openlabel phase, the ITT observed analysis was also
performed, and this analysis included all data
collected, regardless of any treatment switches, with no
imputations performed for missing values. The safety
analysis was based on all subjects exposed to at least
one dose of study drug.
ITT missing equals failure and as-treated analyses
were performed for the proportions of subjects with
plasma HIV-1 RNA levels of <400 and <50 copies/ml.
The primary analysis was the ITT missing equals
failure analysis of the proportion of subjects with HIV1 RNA levels of <400 copies/ml. The time-to-event
analysis was performed for the ITT population. ITT
observed analysis was performed for the median
change from baseline in plasma HIV-1 RNA levels and
CD4 cell counts.
Treatment differences in the proportion of subjects
with plasma HIV-1 RNA levels of <400 copies/ml at
week 48 were analysed using the Cochran Mantel
Haenszel test, controlling for randomization strata,
and across randomization strata using Fisher’s exact
test. The distribution of time-to-event data was estimated using the Kaplan–Meier product-limit survival
method and treatment differences were assessed using
a permutation-based log-rank test. Subjects who never
achieved plasma HIV-1 RNA levels of <400 copies/ml
were considered failures at day 1. Treatment differences in the incidence of adverse events were analysed
by the Fisher’s exact test.
Results
This study was conducted between February 1997 and
November 1998. A total of 232 subjects (116 per treatment group) were randomized into the study.
Demographics and baseline characteristics were
comparable in both groups (Table 1).
Of the 232 subjects who were randomized, four
subjects and seven subjects in the amprenavir/lamivudine/zidovudine and lamivudine/zidovudine groups,
respectively, did not initiate treatment. Of the 112
subjects who received treatment in the amprenavir/
lamivudine/zidovudine group, 63 subjects (56%)
discontinued randomized treatment and the primary
reasons for discontinuation included adverse events
Antiviral Therapy 5:3
Table 1. Demographics and baseline characteristics of
randomized subjects
APV/3TC/ZDV
3TC/ZDV
Characteristic
(n=116)
(n=116)
Age (years)
Median (range)
35 (17–62)
35 (21–62)
Gender (%)
Male
89
89
Female
11
11
Ethnic origin (%)
White
77
73
Black
12
9
Other
11
18
CDC disease status (%)
Category A (asymptomatic)
78
80
Category B (symptomatic, not AIDS)
18
20
Category C (AIDS)
4
0
Plasma HIV-1 RNA (log10 copies/ml)
Median (range)
4.61 (3.61–6.09) 4.74 (3.06–6.31)
CD4 cell count (×106 cells/l)
Median (range)
442 (216–1800) 410 (139–984)
APV, amprenavir (1200 mg bid); 3TC, lamivudine (150 mg bid); ZDV, zidovudine
(300 mg bid); bid = twice daily.
(17%), meeting switch criterion (14%), withdrawal of
consent (9%), lost to follow-up (9%), other unspecified reasons (9%) and protocol violation (<1%). Of the
109 subjects who received treatment in the lamivudine/
zidovudine group, 103 subjects (95%) discontinued
randomized treatment and the primary reasons for
discontinuation included meeting protocol-defined
switch criterion (78%), withdrawal of consent (6%),
adverse events (5%), lost to follow-up (4%) and other
unspecified reasons (4%). Of the subjects who discontinued randomized treatment, 21 subjects (33%) in the
amprenavir/lamivudine/zidovudine group and 87
subjects (84%) in the lamivudine/zidovudine group
entered the open-label phase of the study.
Proportion of subjects with plasma HIV-1 RNA levels
of <400 copies/ml
At week 16, the proportion of subjects with HIV-1
RNA levels of <400 copies/ml was significantly greater
in the amprenavir/lamivudine/zidovudine group
compared with the lamivudine/zidovudine group: 55%
(64/116) versus 15% (17/116) by ITT missing equals
failure analysis and 87% (67/77) versus 20% (19/94)
by the as-treated analysis. By week 48, the proportion
of subjects with HIV-1 RNA of <400 copies/ml was
also significantly greater in the amprenavir/lamivudine/zidovudine group than in the lamivudine/
zidovudine group: 41% (48/116) versus 3% (4/116) by
ITT missing equals failure analysis (P<0.001) and 93%
(50/54) versus 42% (5/12) by as-treated analysis
(P<0.001) (Figures 1a and b). A significant difference
(P<0.001) was observed in each of the three randomization strata at week 48 by the ITT missing equals
failure analysis: 51% (19/37) versus 8% (3/37) for the
HIV-1 RNA 10 000–30 000 copies/ml stratum; 42%
217
JC Goodgame et al.
Figure 1. Proportion of subjects with plasma HIV-1 RNA levels of <400 copies/ml (a, b) and 50 copies/ml (c, d) in the amprenavir
plus lamivudine plus zidovudine and lamivudine plus zidovudine groups over 48 weeks of treatment
Percentage of subjects with HIV-1 RNA <400 copies/ml
(a)
(b)
APV/3TC/ZDV
100
Percentage of subjects with HIV-1 RNA
<400 copies/ml (as-treated analysis)
3TC/ZDV
80
60
40
20
0
0
4
8
12
16
20
24
28
32
36
40
44
60
40
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Study week
No. of subjects
APV/3TC/ZDV
100 91
82
77
73
68
60 60
53
50
53
54
3TC/ZDV
102 98
96
94
86
33
26 15
14
14
13
12
24
32
(c)
(d)
100
Percentage of subjects with HIV-1 RNA <50 copies/ml
Subjects with HIV-1 RNA <50 copies/ml
80
48
Study week
APV/3TC/ZDV
3TC/ZDV
80
60
40
20
0
0
100
8
16
24
32
40
100
80
60
40
20
0
0
48
8
16
40
48
Study week
Study week
APV/3TC/ZDV
107
78
68
59
54
52
3TC/ZDV
109
96
30
16
13
11
ITT missing equals failure analysis (a) and as-treated analysis (b).
APV, amprenavir; 3TC, lamivudine; ZDV, zidovudine.
(23/55) versus 2% (1/55) for the HIV-1 RNA
30 000–100 000 copies/ml stratum; 25% (6/24) versus
0% (0/24) for the HIV-1 RNA >100 000 copies/ml
stratum.
Proportion of subjects with plasma HIV-1 RNA levels
of <50 copies/ml
A greater proportion of subjects receiving amprenavir/lamivudine/zidovudine had plasma HIV-1 RNA
of <50 copies/ml at week 48 compared with those
receiving lamivudine/zidovudine: 34% (40/116) versus
1% (1/116) by ITT missing equals failure analysis and
79% (41/52) versus 9% (1/11) by as-treated analysis
218
(Figures 1c and d).
Plasma HIV-1 RNA profiles
In both treatment groups, the ITT observed analysis
showed median reductions from baseline plasma HIV1 RNA of approximately 2 log10 copies/ml by week 4
(Figure 2). These reductions were maintained in the
amprenavir/lamivudine/zidovudine group through
week 48, but diminished after week 4 in the lamivudine/zidovudine group. Following therapy switches,
the median reduction from baseline plasma HIV-1
RNA increased in the lamivudine/zidovudine group
from week 24 (1.8 log10 copies/ml) to week 48 (2.1
©2000 International Medical Press
Efficacy of amprenavir with lamivudine and zidovudine versus lamivudine and zidovudine alone
Median change from baseline in log10 HIV-1 RNA (copies/ml)
Figure 2. Median change from baseline in plasma HIV-1 RNA (log10 copies/ml) through week 48 in the amprenavir plus
lamivudine plus zidovudine and lamivudine plus zidovudine groups
Randomized therapy
Open-label therapy
-0.5
-1
-1.5
-2
-2.5
-3
0
4
8
12
16
No. of subjects
20
24
28
Study week
32
36
40
44
48
APV/3TC/ZDV 116
104
101
101
99
91
93
85
79
77
77
75
74
3TC/ZDV
104
100
94
88
81
83
71
70
67
68
69
71
116
Error bars are the 25th and 75th percentiles. The values shown for week 16 onwards include subjects with HIV-1 RNA levels of ≥400 copies/ml who had switched to
open-label therapy. Plasma HIV-1 RNA limit of detection was 400 copies/ml.
log10 copies/ml).
CD4 cell counts
CD4 cell counts increased in both treatment groups
throughout the study. At week 48, a median increase of
128×106 cells/l (range, –237–549) and 125×106 cells/l
(range, –194–393) was observed in the amprenavir/
lamivudine/zidovudine and lamivudine/zidovudine
groups, respectively (Figure 3).
Time-to-event analysis
The survival curves for the two treatment groups (Figure
4) were significantly different (P<0.001), with longer
times-to-event observed in the amprenavir/
lamivudine/zidovudine group compared with the
lamivudine/zidovudine group (median time to event of
33 versus 20 weeks). By week 48, the proportions of
subjects who did not have an event were 47 and 10% in
the amprenavir/lamivudine/zidovudine and lamivudine/zidovudine groups, respectively. Most events either
occurred at day 1 (amprenavir/lamivudine/zidovudine
22%; lamivudine/zidovudine 35%) due to subjects never
achieving plasma HIV-1 RNA levels of <400 copies/ml
or never being treated, or at week 20 (amprenavir/
lamivudine/zidovudine 3%; lamivudine/zidovudine
31%) due to subjects switching to open-label therapy.
Antiviral Therapy 5:3
Adverse events
The overall incidence of adverse events was significantly greater in the amprenavir/lamivudine/
zidovudine group compared with the lamivudine/
zidovudine group (100 versus 94%; P=0.013). The
incidence of drug-related nausea, vomiting, rash and
oral/perioral paresthesia was significantly higher in the
amprenavir/lamivudine/zidovudine group compared
with the lamivudine/zidovudine group (P<0.01; Table
2). Most of the adverse events were of mild (amprenavir/lamivudine/zidovudine
27%;
lamivudine/
zidovudine 34%) or moderate (amprenavir/lamivudine/zidovudine 49%; lamivudine/zidovudine 35%)
intensity.
The most common adverse events that led to study
drug discontinuation were nausea (amprenavir/lamivudine/zidovudine 12%; lamivudine/zidovudine <1%),
vomiting (amprenavir/lamivudine/zidovudine 5%) and
rash (amprenavir/lamivudine/zidovudine 3%; lamivudine/zidovudine <1%). The median times to onset of
these adverse events were 4 days for nausea, 33 days
for vomiting and 11 days for rash. The median durations were 24 days for nausea, 5 days for vomiting and
10 days for rash. In the amprenavir/lamivudine/zidovudine group, 31 subjects (27%) reported 36 episodes of
rash that did not result in discontinuation of study
219
JC Goodgame et al.
Figure 3. Median change from baseline in CD4 cell count (cells/mm3) through week 48 in the amprenavir plus lamivudine plus
zidovudine and lamivudine plus zidovudine groups
Randomized therapy
Open-label therapy
220
Median change from baseline in CD4 cell
3
count
(ce’’s/mm )
200
180
160
140
120
100
80
60
40
20
0
–20
–40
–60
Baseline 4
8
12
16
20 24 28
Study week
32
36
40
44
48
No. of subjects (ITT observed analysis)
APV/3TC/ZDV
116 104
100
93
86
78
69
66
67
3TC/ZDV
116 104
103
101 93
88
82
76
71
Error bars are the 25th and 75th percentiles. The values shown for week 16 onwards include subjects with HIV-1 RNA levels of ≥400 copies/ml who had switched to
open-label therapy.
APV, amprenavir; 3TC, lamivudine; ZDV, zidovudine.
Figure 4. Kaplan–Meier survival plot of time-to-event
1.0
0.9
0.8
Probability
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88
Time to event (weeks)
Treatment:
Placebo
Amprenavir
Event defined as plasma HIV-1 RNA level >400 copies/ml, permanent discontinuation of randomized therapy, progression to a new confirmed CDC category C event
or death, in the ITT population.
Notation: placebo (lamivudine/zidovudine group); amprenavir (amprenavir/lamivudine/zidovudine group).
220
©2000 International Medical Press
Efficacy of amprenavir with lamivudine and zidovudine versus lamivudine and zidovudine alone
Table 2. Drug-related adverse events [n (%)] reported by ≥10% of all subjects and grade 3 or 4 adverse events over 48 weeks
All grades*
APV/3TC/ZDV
Adverse event
Nausea
Gaseous symptoms
Fatigue
Headache
Vomiting
Diarrhoea
Paresthesia (oral/perioral)
Rash
Loose stools
Abdominal discomfort
Constipation
Taste disorders
Grade 3 or 4
3TC/ZDV
APV/3TC/ZDV
3TC/ZDV
(n=113)
(n=109)
(n=113)
(n=109)
84 (74%)
36 (32%)
37 (33%)
25 (22%)
34 (30%)
30 (27%)
29 (26%)
28 (25%)
12 (11%)
11 (10%)
6 (5%)
11 (10%)
49 (45%)
47 (43%)
33 (30%)
31 (28%)
15 (14%)
17 (16%)
7 (6%)
5 (5%)
16 (15%)
12 (11%)
14 (13%)
6 (6%)
6 (5%)
0
3 (3%)
0
1 (<1%)
2 (2%)
0
3 (3%)
0
1 (<1%)
0
0
2 (2%)
1 (<1%)
2 (2%)
2 (2%)
0
1 (<1%)
0
0
0
0
0
0
APV, amprenavir (1200 mg bid); 3TC, lamivudine (150 mg bid); ZDV, zidovudine (300 mg bid); bid, twice daily.
*Data for one placebo subject who inadvertently received APV for 8 weeks are included in both treatment groups.
P<0.01 compared with the lamivudine/zidovudine group.
drug in the majority of subjects. In 44% of the cases of
rash, study medication was temporarily withheld. In
only one of these cases did a subject have a recurrence
of rash after re-initiating the study drug.
The number of subjects with a grade 3/4 laboratory
abnormality is presented in Table 3. The incidence of
grade 3/4 laboratory abnormalities was low (≤6%) and
comparable between treatment groups. Overall, a total
of 32 subjects (15%) had at least one grade 3/4 laboratory abnormality over the 48-week period (amprenavir/
lamivudine/zidovudine 14%; lamivudine/zidovudine
15%). The most common clinical chemistry abnormality was elevated serum transaminases. The most
common haematological abnormality was neutropenia.
Cholesterol, triglycerides and glucose levels were
not obtained under fasting conditions during the study.
No grade 3/4 hypercholesterolaemia was observed in
either treatment group. Median baseline cholesterol
values were 167 and 163 mg/dl for the amprenavir/
lamivudine/zidovudine and lamivudine/zidovudine
groups, respectively. Median increases from baseline in
cholesterol of 10.8 mg/dl (week 1) and 23.2 mg/dl
(week 48) were observed in the amprenavir/lamivudine/zidovudine group but no change was observed in
the lamivudine/zidovudine group. Grade 3/4 hypertriglyceridaemia was observed in one subject treated
with lamivudine/zidovudine during the randomized
phase and in three subjects during the open-label
phase, whereas no grade 3/4 hypertriglyceridaemia was
reported in the amprenavir/lamivudine/zidovudine
group. Other clinically significant adverse events that
were considered to be drug-related in subjects treated
with amprenavir/lamivudine/zidovudine included
grade 4 hyperglycaemia in one subject with a family
Antiviral Therapy 5:3
history of diabetes mellitus after 20 weeks of treatment
and haemolytic anaemia in one subject after 12 weeks
of treatment. One subject randomized to lamivudine/
zidovudine who switched on day 285 after initiation of
the study to quadruple therapy with amprenavir/
lamivudine/zidovudine/ abacavir developed a dorsocervical fat accumulation (‘buffalo hump’) on day 424
after initiation of the study.
Discussion
In antiretroviral-naive HIV-1-infected subjects, a
greater proportion of subjects treated with the combiTable 3. Number (%) of subjects with grade 3 or 4
treatment-emergent laboratory abnormalities over 48 weeks*
Parameter
Clinical chemistry
↑ALT
↑AST
↑ALT and/or AST
↑Amylase
↑Bilirubin
↑Glucose
↑Triglycerides
↑Cholesterol
Haematology
↓Haemoglobin
↓Neutrophil count
↓Total WBC
APV/3TC/ZDV
(n=113)
3TC/ZDV
(n=109)
5 (5%)
4 (4%)
6 (6%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
2 (2%)
2 (2%)
3 (3%)
2 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
6 (5%)
1 (<1%)
2 (2%)
7 (6%)
1 (<1%)
Abbreviations: APV, amprenavir (1200 mg BID); 3TC, lamivudine (150 mg BID);
ZDV, zidovudine (300 mg BID); BID, twice daily.
*Data for one placebo subject who inadvertently received APV for 8 weeks are
included in both treatment groups.
221
JC Goodgame et al.
nation of amprenavir, zidovudine and lamivudine had
plasma HIV-1 RNA below detectable levels (<400 and
<50 copies/ml) than subjects receiving lamivudine and
zidovudine, after 48 weeks of treatment. Subjects who
switched to an open-label amprenavir-containing
regimen after 16 weeks demonstrated an immediate
and durable response in both plasma HIV-1 RNA
levels and CD4 cell count over 48 weeks of therapy.
Subjects in the amprenavir/lamivudine/zidovudine
group had longer times-to-event compared with the
lamivudine/zidovudine group. CD4 cell counts
increased throughout the study and the increases were
generally comparable between treatment groups after
48 weeks of treatment.
This study had a number of key considerations.
Firstly, the study was designed with a dual nucleoside
regimen for the first 16 weeks. At the time the study
was designed, the dual nucleoside regimen was considered the standard of care for initial antiretroviral
treatment. In view of the emerging data about the
potency and efficacy of triple therapy with two nucleosides and a PI [24], patients were given the option to
switch their antiretroviral therapy to include openlabel amprenavir and/or switch to other antiretrovirals
after 16 weeks of therapy or if they were experiencing
virological failure. Most of the patients (84%) chose to
alter their therapy. Secondly, as demonstrated by Hill et
al. [25], the efficacy rates as indicated by the proportion of patients with HIV-1 RNA levels below the limit
of quantification vary according to the statistical
methods used. Thus, we performed several statistical
analyses in our study to provide a more complete
understanding of the efficacy of the regimens evaluated, consistent with the design of our study.
The results of our study are generally consistent
with those recently reported in similar protease-naive
populations receiving PI-containing triple regimens
[26–28]. Mitsuyasu et al. [26] reported that after 16
weeks of treatment with the soft gelatin capsule formulation of saquinavir and two NRTIs, the proportion of
subjects with plasma HIV-1 RNA levels below the limit
of detection was 67% (<400 copies/ml) and 37% (<50
copies/ml) using an ITT analysis. In the double-blind,
placebo-controlled AVANTI 2 study [27], the indinavir/lamivudine/zidovudine regimen was compared to
the lamivudine/zidovudine regimen, with the former
regimen showing a superior response in the proportion
of subjects with plasma HIV-1 RNA levels <500
copies/ml (60 versus 18%) and <20 copies/ml (46
versus 4%) at week 52 by the ITT (missing equals
failure) analysis. In the open-label START I trial [28],
a comparison of the stavudine/didanosine/indinavir
regimen to the indinavir/lamivudine/zidovudine
regimen indicated comparable results for the proportion of subjects with plasma HIV-1 RNA levels <500
222
copies/ml (53 versus 52%) and <50 copies/ml (49
versus 47%) at week 48.
When evaluating HIV-1 RNA response across the
three randomization strata with different baseline HIV1 RNA levels, the proportion of subjects with HIV-1
RNA <400 copies/ml among those with baseline HIV1 RNA levels of >100 000 copies/ml was lower
compared with those observed for the other two strata.
Few subjects (n=24) were in this stratum. Therefore,
these data should be viewed with caution. Larger,
controlled studies will be needed to better differentiate
and understand the effects of therapy among subjects
with varying HIV-1 RNA levels and CD4 cell counts.
Combination therapy with amprenavir, lamivudine
and zidovudine was safe and generally well tolerated
over at least 48 weeks. However, since the median
duration of exposure to triple therapy was greater than
to double therapy, subjects receiving the triple combination had a greater probability of experiencing
adverse events. As with the other currently approved
HIV-1 PIs, gastrointestinal symptoms were the most
common adverse events reported in subjects receiving
amprenavir/lamivudine/zidovudine. The greater
percentage
of
subjects
discontinuing
amprenavir/lamivudine/zidovudine treatment was
primarily attributed to mild-to-moderate (grades 1–2)
adverse events.
The safety profile of amprenavir described in the
present study is consistent with that observed in 30
other trials of varying sizes conducted among a total of
1477 diverse group of patients who were treated with
amprenavir in combination with other antiretrovirals
[21]. In these trials, most adverse events were mild-tomoderate, transient and rarely treatment-limiting. The
most frequently reported adverse events were gastrointestinal in nature. Grade 3/4 laboratory
abnormalities, including lipid or glucose abnormalities,
and cases of fat redistribution occurred infrequently,
although as in other studies with PIs until recently, fat
redistribution was not an end-point.
Distinctive and treatment-limiting toxicities have
been associated with the currently marketed protease
inhibitors including nephrolithiasis with indinavir [29],
diarrhoea with nelfinavir [30], nausea, vomiting and
abdominal pain with ritonavir [17], and nausea and
diarrhoea with the soft gelatin capsule formulation of
saquinavir [17]. In the present study, amprenavir
therapy was mostly associated with mild-to-moderate
adverse events. Nausea was the most common treatment-limiting adverse event. Mild-to-moderate rash
occurred most commonly during the second week of
therapy, and was almost always maculopapular, with
or without pruritis. It was not accompanied by fever
and subjects were generally able to continue treatment
through the event. Oral/perioral paresthesia was
©2000 International Medical Press
Efficacy of amprenavir with lamivudine and zidovudine versus lamivudine and zidovudine alone
usually mild and not treatment-limiting. The incidence
of grade 3/4 adverse events reportedly associated with
the use of PI-containing regimens, such as
hypertriglyceridaemia, hypercholesterolaemia, hyperglycaemia, diabetes mellitus, haemolytic anaemia and
lipodystrophy, was low.
Studies have shown that when ritonavir is coadministered with other PIs the plasma concentrations of the
coadministered PI increase [31–34]. Thus, studies have
been conducted to study the interaction between ritonavir and amprenavir. Results indicate that ritonavir
causes clinically significant increases in amprenavir
plasma concentrations [35]. The combination of twice
daily 600 mg amprenavir with 100 mg ritonavir, or
once daily 1200 mg amprenavir with 200 mg ritonavir,
was predicted to increase amprenavir trough concentrations to levels significantly above the mean IC50 for
amprenavir- or multiple PI-resistant viruses [36]. These
dosage regimens as well as the development of the
amprenavir prodrug [37–39] offer the potential for
improved potency concurrently with reductions in
dosing frequency and pill count.
The results of this study confirm that amprenavir in
combination with NRTIs is potent, successfully
achieving plasma HIV-1 RNA levels <400 copies/ml in
a significant number of antiretroviral therapy-naive
subjects. With its potent and durable antiviral effect,
safety and the convenience of twice-daily dosing
without dietary requirements, amprenavir, when
administered in combination with other antiretroviral
agents, should prove to be an important therapeutic
option for HIV-1-infected patients.
Acknowledgments
We thank all of the participating subjects and the
following individuals for their contributions to the
study: Amprenavir PROAB3001 Study Team
Investigators and Staff; Harold A Kessler, MD,
Chicago Center for Clinical Research, Chicago, Ill,
USA; Calvin Cohen, MD, Community Research
Initiative of New England, Brookline, Mass., USA;
Steven Davis, MD, ID Associates, Dallas, Tex., USA;
Ramon A Torres, MD, AIDS Center, St. Vincent’s
Hospital, NY, USA; Danny Lancaster, MD, Methodist
Hospital, Memphis, Tenn., USA; Susan Swindells, MD,
UNMC, Omaha, N.E., USA; Bruce Rashbaum, MD,
Washington DC, USA; Robert Anderson, BS, Pacific
Oaks Research, Beverly Hills, Calif., USA; Jarlath
Black, RN, and Josette Robinson, RAII, University of
Cincinnati, Cincinnati, Ohio, USA; Graham Lovell,
Central Florida Research Initiative, Altamonte Springs,
Fla., USA; Schlomo Staszewski, MD, Klinikum der
Johann Wolfgang Goethe-Universitat, Frankfurt,
Germany; Panagiotis Gargalianos-Kakolyris, MD,
Antiviral Therapy 5:3
General Hospital of Athens, Athens, Greece; Johan N.
Brunn, MD, Infeksjonsmedisinsk avdeling, Ulleval
Sykehus, Norway; Rui Proenca, MD, Servico de
Doencas Infecciosas, Hospital Curry Cabral, Lisbon,
Portugal; Melico Silvestre, MD, PhD, Departmento de
Doencas Infecciosas, Hospitais da Univeridade de
Coimbra, Coimbra, Portugal; Jose Mallolas Masferrer,
MD, Servicio de Enfermedades Infecciosas, Hospital
Clinic i Provincial, Barcelona, Spain; Bonaventura
Clotet Sala, MD, Hospital Germans Trias i Pujol,
Barcelona, Spain; Edmund GL Wilkins, MD,
Department of Infectious Diseases & Tropical
Medicine, North Crumpsall General Hospital,
Crumpsall, Manchester, UK; Chris Taylor, MD,
Directorate of Genitourinary Medicine, The Caldecott
Center, London, UK; Anton Pozniak, MD, FRCP,
Kings College Hospital, London, UK.
Glaxo Wellcome team members: Judith Millard,
PhD for the clinical conduct of the study; Barbara
McGarry, MS, Kamlesh Patel, BSc (Hons), and
Michelle Cartland, BS, MAT, for data management.
Supported by a grant from Glaxo Wellcome
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