World Journal of AIDS, 2012, 2, 245-251
doi:10.4236/wja.2012.23032 Published Online September 2012 (
Trizivir (Abacavir/Lamivudine/Zidovudine) plus
Lopinavir/Ritonavir Induction Therapy Followed by
Trizivir-Alone Maintenance for HIV-1-Infected Patients:
A 96-Week Pilot Treatment Simplification Study
Joseph C. Gathe1*, Dean T. Martin2, M. Keith Rawlings3, Benjamin Daquioag1, John E. Fuchs4,
Vanessa C. Williams4, Katrina L. Oie4, Gary E. Pakes4
1Therapeutic Concepts P.A., Houston, USA; 2Cigna Healthcare Corp., Phoenix, USA; 3Peabody Clinic, Dallas, USA; 4Glaxo-
SmithKline, Research Triangle Park, Durham, USA.
Email: *
Received December 17th, 2011; revised February 21st, 2012; accepted May 18th, 2012
Objective: The purpose of this study was to investigate whether switching HIV-infected patients stabilized on Trizivir
(abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg) plus lopinavir/ritonavir 400 mg/100mg twice daily to
Trizivir alone affects clinical efficacy and tolerability. Methods: This phase 4, open-label, pilot study was conducted
over 96 weeks in 23 antiretroviral-naïve, HIV-infected patients. Initially, these patients received induction therapy with
Trizivir plus lopinavir/ritonavir 400 mg/100mg twice daily. Patients who achieved a viral load < 50 copies/mL at week
36 or 44 started maintenance therapy with Trizivir alone at week 48 and continued this regimen through week 96. Re-
sults: The study population was a median of 37 years of age, predominantly male (78%) and African American (61%,
with 39% Caucasians), and had a baseline mean viral load of 5.45 log10 copies/mL and CD4+ count of 232 cells/mm3.
Nineteen patients completed induction; of the four who did not, three were lost to follow-up and one withdrew due to
gastrointestinal adverse events. In 14 induction completers who had viral load measurements taken at week 48, in-
tent-to-treat: observed analysis showed a week 48 viral load < 400 copies/mL attained in 100% (14/14) and <50 cop-
ies/mL attained in 71% (10/14). Median week 48 CD4+ cell count was 192 cells/mm3 higher than the baseline count.
Twelve patients completed the subsequent 48-week Trizivir-alone maintenance phase, of whom 11 (92%) achieved vi-
ral loads of both <400 and <50 copies/mL at week 96. Median week 96 CD4+ cell count was 208 cells/mm3 above
baseline. Trizivir-only maintenance was associated with fewer adverse events than the Trizivir-lopinavir/ritonavir in-
duction phase and with improvement in total cholesterol, LDL-cholesterol, and triglycerides. Conclusions: Trizivir-alone
maintenance after Trizivir-lopinavir/ritonavir induction maintained virologic and CD4+ cell response, and was associ-
ated with an improved adverse event and lipid profile.
Keywords: Abacavir/Lamivudine/Zidovudine; HIV-1 Infection; Induction-Maintenance Strategy; Kaletra;
Lopinavir/Ritonavir; Trizivir
1. Introduction
The induction-maintenance antiretroviral treatment
strategy involves giving HIV-infected patients induction
therapy with multiple antiretroviral agents to achieve
virologic suppression, then follow this by deletion of an
agent of one class to simplify the regimen. In HIV care,
the induction-maintenance strategy was first explored in
the late 1990s using different combinations of nucleoside
reverse transcriptase inhibitors (NRTIs), non-nucleoside
reverse transcriptase inhibitors (NNRTIs), and protease
inhibitors (PI) [1]. Antiretroviral induction-maintenance
regimen sequences investigated in clinical trials to date
have included switching a double NRTI/double PI regi-
men to a double PI-alone or a single NRTI/single PI
combination [2]; a double NRTI/single PI regimen to ei-
ther a double NRTI-alone or double PI-alone regimen [3];
a ritonavir-boosted PI/double NRTI regimen to a boosted
PI-alone regimen [4-9]; and a triple NRTI/single NNRTI
combination to a triple NRTI-alone regimen [10,11].
The triple NRTI fixed-dose combination Trizivir
(GlaxoSmithKline, Research Triangle Park, North Caro-
lina, USA), which contains abacavir 300 mg, lamivudine
*Corresponding author.
Copyright © 2012 SciRes. WJA
Trizivir (Abacavir/Lamivudine/Zidovudine) plus Lopinavir/ Ritonavir Induction Therapy Followed by Trizivir-Alone
Maintenance for HIV-1-Infected Patients: A 96-Week Pilot Treatment Simplification Study
150 mg, and zidovudine 300 mg per tablet, has been
available for twice-daily treatment of HIV infection since
the late 1990s [12]. Use of Trizivir was expected to pre-
serve antiretroviral agents of other classes for later use,
thereby potentially delaying resistance development. Tri-
zivir also offered dose symmetry with other agents simi-
larly administered twice daily. Although current antiret-
roviral treatment guidelines from the Department of
Health and Human Services and IAS-USA do not rec-
ommend monotherapy with a triple NRTI combination
like Trizivir for initiating antiretroviral therapy [13,14],
Trizivir-alone maintenance could be considered by clini-
cians desiring to avoid particular adverse events some-
times associated with recommended drug regimens.
Induction with a triple NRTI plus a boosted PI, fol-
lowed by deletion of the PI has undergone little study
[15-17]. In view of this data gap, the focus of the present
study was to evaluate the efficacy and tolerability of in-
duction with Trizivir as the triple NRTI component and
lopinavir/ritonavir (LPV/r) as the PI component, fol-
lowed by a maintenance period of Trizivir alone.
2. Methods
This phase 4 multicenter, open-label, single-arm, pilot
study was conducted at three US-based treatment sites:
Therapeutic Concepts P.A. (Houston, Texas), Cigna
Healthcare Corp (Phoenix, Arizona), and the Peabody
Clinic (Dallas Texas). Patients could be enrolled if they
were HIV-infected, as documented by HIV-1 antibody
enzyme-linked immunosorbent assay (ELISA) and con-
firmed by Western blot or HIV plasma viremia, were
aged 13 years or older, had screening HIV-1 RNA
20,000 copies/mL, and were antiretroviral-naïve (defined
as having <2 weeks of prior treatment with any NRTI
and no exposure to PIs). Women of child-bearing poten-
tial could be considered for the study if they had a nega-
tive serum pregnancy test (β-human chorionic gonad-
otropin) at screening and practiced birth control (used
double barrier method of contraception or intrauterine
device, or were abstinent) throughout the study. There
were no CD4+ cell count restrictions on eligibility.
Key exclusion criteria included: active AIDS-defining
opportunistic infection or disease (CDC Category C) or
pre-existing mental, physical, or substance abuse disorder
which, in the opinion of the investigator, would preclude
the patient from participation; use of immunomodulators,
systemic cytotoxic chemotherapy, or radiation therapy
within 4 weeks prior to study entry; exposure to an HIV
vaccine within 3 months prior to study entry; clinically
relevant hepatitis within 6 months prior to screening; or
concurrent use of any agent known to have a phar-
macologic interaction with the boosted PI. All patients
provided written informed consent to participate in the
study, and the protocol was approved by the institutional
review boards for the study sites. The study was con-
ducted according to Good Clinical Practice and the 2000
Helsinki Declaration.
During the induction phase of the study (baseline
through week 48), the patients received one Trizivir tab-
let plus one LPV/r 400/100 mg fixed-dose combination
capsule (Kaletra®, Abbott Laboratories, North Chicago,
Illinois) twice daily. Patients achieving a viral load
(HIV-1 RNA) < 50 copies/mL at weeks 36 and 44 were
eligible to enroll in the maintenance phase, during which
LPV/r was discontinued at week 48 and Trizivir alone
was continued through week 96.
Patients were evaluated during the induction phase at
weeks 1, 2, 4, 8, 16, 24, 36, 44, and 48, and during the
maintenance phase at weeks 56, 64, 72, 84, and 96. Rou-
tine biochemistry, hematology, and immunology tests
were conducted at each assessment. The severity of ad-
verse events was graded according to DAIDS criteria
[18]. If any patient were to develop a suspected abacavir-
related hypersensitivity reaction, Trizivir was to be dis-
continued immediately. Median lipid values were as-
sessed as to whether they exceeded the National Choles-
terol Education Program (NCEP) cutoff levels at which
hypolipidemic drug therapy would be indicated [19].
Viral load was measured using the Roche Amplicor
MONITOR Ultrasensitive assay (version 1.5; lower limit
of quantitation [LLOQ] 50 copies/mL) (Roche Diagnos-
tics, Branchburg, New Jersey) and HIV-1 MONITOR
Version 1.0 polymerase chain reaction (PCR) assay
(LLOQ, 400 copies/mL) (Roche, Nutley, New Jersey).
CD4+ lymphocyte cell count was assessed by flow cy-
tometry. Adherence was monitored by a self-dministered
questionnaire, the PMAQ3 [20].
The primary endpoint of the study was the proportion
of patients with plasma HIV-1 RNA < 50 copies/mL at
the end of the maintenance phase (week 96). Treatment
failure was defined as either virologic failure (repeated
[consecutive] detection of plasma HIV-1 RNA > 500
copies/mL after having achieved an HIV-1 RNA < 50
copies/mL) or discontinuation because of toxicity, clini-
cal disease progression, or death. For virologic response,
both intent-to-treat: missing equals failure (ITT: M = F)
and observed analyses were performed. All other pa-
rameters were reported using observed analyses only.
Descriptive-only statistical analyses were applied to ef-
ficacy and safety data and comparisons.
3. Results
3.1. Patient Characteristics
A total of 23 patients were enrolled at the three study
sites. Most of the patients (18 [78%]) were males and
Copyright © 2012 SciRes. WJA
Trizivir (Abacavir/Lamivudine/Zidovudine) plus Lopinavir/ Ritonavir Induction Therapy Followed by Trizivir-Alone
Maintenance for HIV-1-Infected Patients: A 96-Week Pilot Treatment Simplification Study
African American (14 [61%], with 9 [39%] Caucasians).
The median age was 37 years (range, 20 to 74 years).
Median baseline plasma HIV-1 RNA level was 5.45 log10
copies/mL (range, 4.28 to 5.88 log10 copies/mL). Nine
patients (39%) had an HIV-1 RNA < 100,000 copies/mL,
and 14 (61%) an HIV-1 RNA 100,000 copies/mL.
Median baseline CD4+ cell count was 232 cells/mm3
(range, 19 to 504 cells/mm3), with 12 (52%) 200
cells/mm3 and 11 (48%) < 200 cells/mm3. The baseline
CDC classification was Category A in 16 patients (70%),
Category B in six (26%), and Category C in one (4%).
3.2. Virologic and Immunologic Response
Of the 23 patients who started induction, 19 completed it,
three were lost to follow-up, and one withdrew due to
grade 2 adverse events (combination of diarrhea/fatigue/
nausea/vomiting). Of the 19 induction completers, 14 had
viral load measurements done at week 48 (five patients
missed their week 48 study visit). Week 48 ITT: observed
analysis indicated viral load < 400 copies/mL in 100% of
the 14 induction completers and < 50 copies/mL in 71%
(10) (Figure 1). ITT: M = F analysis showed these levels
of viral load suppression in 14/23 (61%) and 10/23 (43%),
respectively. As Figure 1 indicates, a drop in percentage of
patients with viral load <50 copies/mL occurred between
week 32 and week 48 that may possibly have been due to
non-adherence in a few patients. Median CD4+ increase
above baseline was 192 cells/mm3 at week 48 (Figure 2).
Figure 1. Proportion of patients with HIV-1 RNA < 50 cop-
Figure 2. Changes in CD4+ cell count.
Nineteen patients entered the maintenance phase of the
study. Twelve patients completed the entire maintenance
phase through week 96, of whom 92% (11/12) achieved
viral loads of <400 and <50 copies/mL in the ITT: ob-
served analysis and 48% (11/23) in the ITT: M = F
analysis (Figure 1). One of the 12 maintenance com-
pleters had an insufficient viral load at his last two study
visits (470 copies/mL at week 84 and 2000 copies/mL at
week 96), and non-adherence may have been a causal
factor for this. Of the seven patients who dropped out of
the maintenance phase prematurely, one had met the cri-
teria of virologic failure with two consecutive viral load
measurements of >500 copies/mL (at weeks 64 and 72),
three had missed their week 96 study visit (all had had a
viral load < 50 copies/mL at every maintenance visit
through week 84), and three had had a single insufficient
viral load at one study visit and subsequently withdrew
from the study. Median change from baseline in CD4+
cell count was +208 cells/mm3 at week 96 (Figure 2).
3.3. Safety and Tolerability
During the study, all 23 patients experienced at least one
adverse event that was grade 1 to 2 (mild to moderate) in
severity. Adverse events that investigators considered to
be treatment-related were reported by 13 patients (57%);
these included diarrhea (two), nausea (four), fatigue
(four), rash (two), abdominal pain (two), vomiting (two),
and alopecia, abdominal distention, upper abdominal
pain, hyperlipidemia, dizziness, erectile dysfunction, and
upper respiratory tract infection (one case each). Most of
these adverse events were reported within the first 30
days of the induction period, with the exceptions being
one report each of diarrhea (at 62 days), fatigue (at 43
days), rash (at 96 days), and upper respiratory tract infec-
tion (at 385 days—the only adverse event reported dur-
ing the maintenance phase). No suspected abacavir-re-
lated hypersensitivity reactions occurred.
Median values of all lipids increased above baseline
values during the Trizivir-LPV/r induction phase and gen-
erally decreased during the Trizivir-only maintenance phase
(Figure 3). Median lipid concentrations at base-line, end of
induction (week 48), and end of maintenance (week 96)
were 165.5, 215.0, and 194.0 mg/dL, respectively, for total
cholesterol; 102.5, 129.5, and 119.5 mg/dL, respectively, for
LDL-cholesterol; 36.5, 45.0, and 39.0 mg/dL, respectively,
for HDL-cholesterol; and 137.0, 208.5, and 141.0 mg/dL,
respectively, for triglycerides. Although median total cho-
lesterol and triglyceride concentrations exceeded the NCEP
cutoff levels at the end of induction, the medians for
these lipids fell below the cutoffs during maintenance. Of
the 12 patients who completed both phases of the study,
the number whose total cholesterol exceeded the NCEP
cutoff (200 mg/dL) at baseline, end of induction, and end of
Copyright © 2012 SciRes. WJA
Trizivir (Abacavir/Lamivudine/Zidovudine) plus Lopinavir/ Ritonavir Induction Therapy Followed by Trizivir-Alone
Maintenance for HIV-1-Infected Patients: A 96-Week Pilot Treatment Simplification Study
Figure 3. Median fasting lipids at baseline, week 48, and
week 96. The cut-off levels established by the NCEP are
shown with dotted lines.
maintenance was five, nine, and six; for LDL-cholesterol
(130 mg/dL), the number was five, seven, and three; for
HDL-cholesterol (40 mg/dL), the number was four, eight,
and five; and for triglycerides (150 mg/dL), the number
was four, nine, and five. All patients whose lipids fell
below the NCEP cut-off levels were able to avoid the
need for hypolipidemic agents.
4. Discussion
This study showed that in HIV-infected patients who
have attained a reduction in viral load to <50 copies/mL
with a Trizivir-LPV/r induction regimen, the deletion of
LPV/r from the regimen with maintenance of Trizivir
alone results in continued virologic suppression, enhanced
CD4+ cell counts, and improved tolerability. The effi-
cacy results of our clinical trial are consistent with those
of two other studies that have evaluated the same regimen
for induction and maintenance [15,16]. Thus, van Raalte
et al. [15] found that 19 (95%) of 20 antiretroviral-naïve
patients with viral loads < 50 copies/mL after Trizivir-
LPV/r induction for a mean of 19 weeks (range, 6 - 39
weeks) retained this level of virologic suppression over a
mean of 36 weeks (range, 6 - 73 weeks) after LPV/r de-
letion and Trizivir-alone continuation. The one patient
who did not achieve < 50 copies/mL during maintenance
was found to be non-adherent. No CD4+ cell data were
presented in the report of this study. Similarly, Mallolas
et al. [16] observed that 48 of 60 patients (80%) with
viral loads < 50 copies/mL after 24 to 36 weeks of
Trizivir-LPV/r induction were able to maintain viral
loads 200 copies/mL and achieve a 274-cell/mm3 me-
dian gain in CD4+ count 48 weeks after deleting LPV/r
(no data on proportion < 50 copies/mL presented). It is
noteworthy that in both of these studies, a variable time
for induction was allowed. In contrast, in our study we
specifically chose week 36 (with confirmation at week
44) to assess eligibility for maintenance therapy (HIV-1
RNA < 50 copies/mL) because this time period is at least
nine times longer than the half-life of the second phase of
viral decay [21].
Comparable efficacy findings during Trizivir-alone
maintenance therapy have been observed in an induction-
maintenance study in which a PI other than LPV/r was
combined with Trizivir for induction [17]. Thus, in
Trisud, 18 patients whose viral load was <50 copies/mL
after 48 weeks of induction with twice-daily Trizivir plus
nelfinavir 1250 mg were switched to Trizivir alone for
the subsequent 48 weeks [17]. Fifteen patients completed
the Trizivir-alone maintenance period, and three patients
withdrew from the study for reasons investigators con-
sidered unrelated to Trizivir (pregnancy, stroke, and
murder, respectively). Of the 15 completers, 11 (79%)
had week 48 viral loads < 50 copies/mL, three had viral
loads < 400 copies/mL, and the other patient did not have
a viral load measurement at week 48 due to her missing
the week 48 clinic visit (although her viral load was <50
copies/mL at week 40). Median CD4+ cell count in-
creased from 336/mm3 at the start of maintenance to
447/mm3 at week 48.
Trizivir-alone maintenance also has been evaluated in
clinical trials in which antiretroviral-naïve patients re-
ceived 3 months of induction with regimens of dual
nucleosides (zidovudine/lamivudine, stavudine/lamivu-
dine, or stavudine/didanosine) plus a PI (indinavir, nelfi-
navir, or LPV/r) followed by Trizivir alone [22-26]. In
these studies, maintenance of viral load and continued
increases in CD4+ counts were generally seen over the
ensuing 48-week or longer Trizivir-alone maintenance
period. However, because these studies were conducted
before it became standard-of-care to test for the presence
of the HLA-B5701 allele (to avoid prescribing abacavir for
HLA-B5701-positive, hypersensitivity-prone patients), dro-
pouts due to suspected abacavir-related hypersensitivity
reactions occurred, which confounded the efficacy results.
Therefore, the applicability of the results of these older
studies to current clinical practice in antiretroviral pre-
scribing is dubious.
Almost all adverse events in our study were reported
during the induction phase, with most reports during the
first month. Only one adverse event (upper respiratory
tract infection) was reported during the Trizivir-alone
maintenance phase; this was considered unlikely to be
treatment-related. Although discontinuation of LPV/r fol-
lowing the induction phase may have accounted for some
diminution in adverse events, this diminution was also
likely impacted by the natural reduction in adverse event
frequency that occurs with longer term therapy [27]. A
natural tendency for improved tolerance over time was
also shown in the CNA3003 study of the components of
Trizivir given in combination twice daily as monotherapy
Copyright © 2012 SciRes. WJA
Trizivir (Abacavir/Lamivudine/Zidovudine) plus Lopinavir/ Ritonavir Induction Therapy Followed by Trizivir-Alone
Maintenance for HIV-1-Infected Patients: A 96-Week Pilot Treatment Simplification Study
[28]. Thus, in the CNA3003 comparison of total inci-
dence of adverse events at weeks 0 (baseline) to 16 ver-
sus at weeks 16 to 48, the following frequency rates were
observed: nausea, 47% vs 8%; malaise/fatigue, 37% vs
8%; headache, 31% vs 13%, and nausea with vomiting,
16% vs 5% [28].
Our study demonstrated that lipids increased during
the Trizivir-LPV/r induction period, but improved after
LPV/r was stopped and Trizivir alone was continued for
maintenance. During induction, median concentrations
for the treatment group rose above NCEP cutoffs for total
cholesterol and triglycerides. Several patients in whom
lipid concentrations exceeded NCEP cutoffs during in-
duction, and hence were candidates for hypolipidemic
agents at that study point, were able to obviate the need
for these agents during Trizivir-alone maintenance be-
cause their lipids fell below NCEP cutoffs in the latter
phase. Mallolas et al. [16] observed a similar pattern of
change in total cholesterol, HDL-cholesterol, and triglyc-
erides during Trizivir-LPV/r induction (median change
from baseline of +30.5, +8, and +65 mg/dL, respectively)
and Trizivir-alone maintenance (median change from end
of induction to end of study of 25, 2.7, and 62 mg/dL,
respectively). Comparable improvement in lipids has also
been reported in studies of patients who have switched
from Trizivir-efavirenz induction to Trizivir-alone main-
tenance [10,11,29].
Our study was limited by its non-randomized design,
the small size of the study population, and the unavail-
ability of resistance information in patients who had in-
sufficient virologic response or failure. However, resis-
tance data from the Mallolas et al. study of Trizivir-
LPV/r induction with Trizivir-alone maintenance re-
vealed that primary treatment-emergent mutations ob-
served in virologic failures were either M184V alone or
M184V plus a thymidine analogue-associated mutation
[16]. Use of a quality-of-life measuring tool also would
have been valuable to detect any changes in patient att-
itudes toward and satisfaction with their antiretroviral
therapy following the change from the induction to the
maintenance regimen.
In conclusion, in this pilot study, Trizivir-alone main-
tenance after Trizivir-LPV/r induction resulted in sus-
tained virologic and CD4+ cell response and an im-
proved adverse event and lipid profile.
5. Acknowledgements
This investigator-initiated study was funded by Glaxo-
SmithKline. We gratefully acknowledge the patients who
participated in this study. We thank Terry Paul, PhD, of
Paul Medical Writing, Inc. for his writing and editorial
assistance in the preparation of the manuscript. Results of
this study were presented in part in Abstract No.
CDB0480 at the XVI International AIDS Conference,
Toronto, Canada, August 13-18, 2006.
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Maintenance for HIV-1-Infected Patients: A 96-Week Pilot Treatment Simplification Study
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CDC: Centers for Disease Control and Prevention;
DAIDS: Division of Acquired Immunodeficiency Syn-
drome (of the United States National Institutes of Health);
LLOQ: lower limit of quantitation;
NCEP: National Cholesterol Education Program;
NNRTI: non-nucleoside reverse transcriptase inhibitor;
NRTI: nucleoside reverse transcriptase inhibitor;
PI: protease inhibitor.
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