Content uploaded by Gerald Pierone
Author content
All content in this area was uploaded by Gerald Pierone on Mar 24, 2016
Content may be subject to copyright.
HIV/AIDS • CID 2006:43 (15 November) • 1337
HIV/AIDSMAJOR ARTICLE
Efficacy of the Protease Inhibitors Tipranavir
plus Ritonavir in Treatment-Experienced Patients:
24-Week Analysis from the RESIST-1 Trial
Joseph Gathe,
1
David A. Cooper,
10
Charles Farthing,
2
Dushyantha Jayaweera,
3
Dorece Norris,
5
Gerald Pierone, Jr.,
6
Corklin R. Steinhart,
4
Benoit Trottier,
8
Sharon L. Walmsley,
9
Cassy Workman,
11
Geoffrey Mukwaya,
7
Veronika Kohlbrenner,
7
Catherine Dohnanyi,
7
Scott McCallister,
7
and Douglas Mayers,
7
for the RESIST-1 Study
Group
a
1
Therapeutic Concepts, Houston, Texas;
2
AIDS Healthcare Foundation, Los Angeles, California;
3
University of Miami School of Medicine and
4
Steinhart Medical Associates, Miami,
5
Comprehensive Research Institute, Tampa, and
6
AIDS Research and Treatment Center of the Treasure
Coast, Fort Pierce, Florida;
7
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut;
8
Centre de Recherche en Toxicologie de
l’Environnement, Universite du Quebec a Montreal, Montreal, and
9
University of Toronto, Ontario, Canada;
10
National Centre in HIV Epidemiology
and Clinical Research, University of New South Wales, and
11
AIDS Research Initiative/Ground Zero Medical, Sydney, Australia
(See the article by Cahn et al. on pages 1347–56)
Background. Improved treatment options are needed for patients infected with multidrug-resistant human
immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral
activity against many protease inhibitor–resistant HIV-1 isolates. The Randomized Evaluation of Strategic Inter-
vention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing
the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted
comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1–infected patients.
Methods. Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America
and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used
to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and
were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined
as a confirmed reduction in the HIV-1 load of ⭓1log
10
less than the baseline level without treatment change at
week 24.
Results. Mean baseline HIV-1 loads and CD4
+
cell counts were 4.74 log
10
copies/mL and 164 cells/mm
3
,
respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a ⭓1-
log
10
reduction in the HIV-1 load (intent-to-treat population; ). Mean increases in the CD4
+
cell countP ! .0001
of 54 and 24 cells/mm
3
occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more
common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate
aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group.
Conclusions. TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-
boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.
Protease inhibitor (PI)–based combination antiretro-
viral therapy has produced significant decreases in mor-
bidity and mortality in patients with HIV-1 infection
[1]; however, treatment failure still occurs [2–5] as a
Received 23 February 2006; accepted 6 July 2006; electronically published 17
October 2006.
a
Members of the study group are listed at the end of the text.
Reprints or correspondence: Dr. Joseph Gathe, Therapeutic Concepts, 4900
Fannin St., PA Houston, TX 77004 (drgathe@josephgathe.com).
Clinical Infectious Diseases 2006; 43:1337–46
2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4310-0019$15.00
result of poor tolerability, lack of adherence, and chal-
lenging dosing regimens, all of which can lead to viral
resistance [6–8]. Such issues may limit options for fu-
ture therapy [9–11], particularly for patients who ex-
perience triple–drug class virologic failure and who may
be at increased risk of death (3-year mortality rate,
15%) [12]. Therefore, despite the undisputed benefits
of modern antiretroviral therapy regimens, newer
agents with activity against drug-resistant HIV-1 are
needed.
Tipranavir is a nonpeptidic PI of the dihydropyrone
sulfonamide class with a structure differing from that
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
1338 • CID 2006:43 (15 November) • HIV/AIDS
of peptidic PIs, and in vitro studies have shown that it may be
effective against virus strains that are resistant to available pep-
tidic PIs [13–18]. Tipranavir is rapidly and extensively metab-
olized through the cytochrome P450 isoenzyme 3A [19–22]
and must be coadministered with ritonavir to attain therapeutic
concentrations [23]. Ritonavir-boosted tipranavir (TPV/r) has
demonstrated potent antiviral activity in both treatment-naive
and treatment-experienced patients [24, 25].
The Randomized Evaluation of Strategic Intervention in
multi-drug reSistant patients with Tipranavir (RESIST-1) trial
is an ongoing, open-label, phase III multicenter study designed
to evaluate the efficacy and safety of TPV/r (500 mg/200 mg
twice per day, selected on the basis of phase II dose-ranging
studies) and an investigator-selected, ritonavir-boosted, stan-
dard-of-care comparator PI (CPI/r), when given with an op-
timized background regimen to treatment-experienced, HIV-
1–infected patients. A similar study (RESIST-2) has been
conducted in Europe and Latin America [26]. The results of
the 24-week interim analysis of RESIST-1 are presented here.
METHODS
Patients. HIV-1–infected adult patients were screened for
baseline HIV-1 RNA levels ⭓1000 copies/mL (i.e., the mini-
mum level required for genotyping); documented baseline ge-
notypic resistance demonstrating ⭓1 primary PI mutation (co-
dons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M) [27]; no
more than 2 PI resistance-associated mutations at codons 33,
82, 84, or 90; at least 3 consecutive months of experience with
all antiretroviral therapy agents (nucleoside reverse-transcrip-
tase inhibitors [NRTIs], nonnucleoside reverse-transcriptase in-
hibitor [NNRTIs], and PIs); experience with ⭓2 PI-based reg-
imens, one of which had to be the regimen at baseline. There
was no restriction with regard to the CD4
+
cell count. Safety
screening laboratory values of the Division of AIDS of the
National Institutes of Health of grade ⭓2 were exclusionary
(grade 2 was allowed for total cholesterol and triglyceride
levels). Other exclusion criteria included interruption in the
antiretroviral treatment regimen for ⭓7 consecutive days within
3 months of screening, prior tipranavir use, a positive preg-
nancy test result, or breast-feeding. Patients were excluded if
they required other investigational medications, immunomo-
dulatory drugs, or ethinyl estradiol within 30 days of study
entry; if they were actively abusing substances that affected
protocol participation; if they had an unacceptable medical
history, as determined by the investigator (e.g., on the basis of
exclusionary chest radiograph or electrocardiograph findings);
or if they were unlikely to survive for 12 months. The protocol
and written informed consent forms were reviewed and ap-
proved by an institutional review board or ethics committee
before patients entered the study.
Study design. This ongoing, randomized, open-label, phase
III study is being conducted at 125 sites in the United States,
Canada, and Australia for a treatment period of 96 weeks. The
main efficacy end point is treatment response, defined as the
proportion of patients with a reduction in the HIV-1 load of
⭓1log
10
after 24 weeks (confirmed by 2 consecutive measure-
ments), without having experienced virologic failure, discon-
tinued treatment with the study PI, introduced new antiret-
roviral agents because of a lack of treatment efficacy, neglected
to maintain follow-up, or died. Other end points included the
change from the baseline value in plasma HIV-1 RNA levels,
achievement of an HIV-1 load
!400 or !50 copies/mL, changes
in the CD4
+
cell count during treatment, and safety measures.
Treatment. Before randomization, investigators selected
both a CPI/r and an NRTI-based and NNRTI-based optimized
background regimen (manufacturer’s recommended dosages)
for each patient on the basis of genotypic resistance screening
findings and the patient’s antiretroviral medication history. An
expert resistance panel was available to help select the CPI/r.
Patients were randomized to receive TPV/r or a preselected
CPI/r (lopinavir-ritonavir, 400 mg/100 mg twice per day; in-
dinavir-ritonavir, 800 mg/100 mg twice per day; saquinavir-
ritonavir, 1000 mg/100 mg or 800 mg/200 mg twice per day;
or amprenavir-ritonavir, 600 mg/100 mg twice per day). Ran-
domization was stratified by both the preselected PI and the
use of enfuvirtide. Tipranavir (250-mg capsules) was supplied
by Boehringer Ingelheim, and CPIs and ritonavir were com-
mercially acquired.
Changes to the treatment regimen were permitted only for
reasons of toxicity and/or intolerance to the non-PI compo-
nents of the regimen. After week 8, patients in the CPI/r arm
had the option of discontinuing the assigned CPI because of a
lack of initial virologic response (defined as a decrease in the
HIV-1 load of
!0.5 log
10
from baseline or failure to achieve an
HIV-1 load of
!100,000 copies/mL despite having a 0.5-log
10
decrease) or confirmed virologic failure (defined as an HIV-1
load of
!1log
10
less than the baseline level confirmed on 2
consecutive assays or as 1 HIV-1 load of
!1log
10
less than the
baseline value followed by a permanent discontinuation of ther-
apy) to receive TPV/r as part of a separate rollover study. This
option was only permitted for participants who experienced
confirmed HIV-1 load failure who had a measurable CPI blood
concentration. Trough plasma drug concentrations for all PIs
and ritonavir were determined at weeks 2, 4, and 28 (i.e., visits
4, 5, and 8). The ratio of the geometric mean trough plasma
concentration for the PI to the IC
50
(both unadjusted and pro-
tein adjusted) of the HIV isolate at study entry was calculated
and correlated to subsequent virologic response.
Sample analysis. Plasma HIV-1 RNA levels were measured
using the Amplicor HIV-1 Monitor Assay, version 1.5 (Roche),
or the UltraSensitive method, version 1.5 (Roche). CD4
+
cell
counts were measured using standard flow cytometry. All tests
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
HIV/AIDS • CID 2006:43 (15 November) • 1339
were conducted by Covance Central Laboratory Services (In-
dianapolis, IN). HIV genotype resistance assessments were per-
formed using the TruGene method, version 1.0, at screening;
at weeks 4, 8, 16, and 24; and at end of treatment. Phenotypic
drug resistance was determined in a randomly selected subset
of 250 patients by Virco NV (Mechelen, Belgium) using Virco’s
Antivirogram assay. The Division of AIDS adverse events scale
was used to grade adverse event intensity and several laboratory
abnormalities, and the Common Toxicity Criteria scale was
used to grade cholesterol levels.
Statistical analysis. Differences in treatment response at
week 24 were analyzed by a 2-sided 95% CI, which was adjusted
for preselected PI and enfuvirtide use [28]. A sample size of
247 patients per treatment arm provided 90% power to detect
15% superiority of tipranavir over CPIs in virologic response
at 24 weeks, using a 2-sided Fisher’s exact test. All efficacy
analyses use the intent-to-treat, noncompleter-considered-fail-
ure analysis, in which missing values associated with premature
discontinuation of treatment were considered to indicate treat-
ment failure. Changes in the HIV-1 load and CD4
+
cell count
over time were evaluated using the last-observation-carried-
forward analysis.
RESULTS
Baseline Patient Characteristics
Between January 2003 and April 2004, a total of 1406 patients
were screened for the RESIST-1 trial, and 630 patients were
randomized (figure 1). Baseline characteristics were comparable
between groups (table 1). The median number of genotypically
available antiretrovirals in the optimized background regimen
was 2 in the TPV/r group and 1 in the CPI/r group, and more
patients in the TPV/r arm exhibited resistance to their prese-
lected PI (54.3% vs. 60.5%). A higher proportion of patients
in the CPI/r group than the TPV/r group had hepatitis C virus
coinfection (7.4% vs. 3.2%).
Baseline Resistance Characteristics
Baseline genotypes identified a mean of 2 primary protease gene
mutations from among 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V,
or 90M, as well as a mean of 15 total protease gene mutations
or polymorphisms. The median baseline phenotypic fold-
change in susceptibility to tipranavir for the random sample
of viral isolates was 1.9 times wild-type IC
50
, compared with
the following CPI IC
50
values for the same specimens: 77.8-
fold for lopinavir, 39.0-fold for indinavir, 27.2-fold for saqui-
navir, and 12.2-fold for amprenavir. The expert resistance panel
was consulted for optimized background regimen selection in
154 (25%) of 620 cases, with 114 (74%) of their 154 recom-
mendations being implemented. The optimized background
regimen included a median of 1 genotypically active antiret-
roviral, including enfuvirtide (range, 0–4 antiretrovirals). The
most common optimized background regimen (not including
the CPI), which was received by 158 patients (25.5%), was 2
NRTIs. On the basis of the genotype test results, 176 patients
(56.6%) in the TPV/r group and 183 patients (59.2%) in the
CPI/r group were assigned a new PI.
Patient Disposition
Overall, 263 patients (84.6%) and 151 patients (48.9%) in the
TPV/r and CPI/r groups, respectively, completed 24 weeks of
treatment (figure 1). More patients in the TPV/r arm (199
patients [64.0%]) than in the CPI/r arm (136 patients [44.0%])
received study medication for at least 24 weeks. This resulted
in a greater number of patient-exposure-years for the TPV/r
arm (133.3 years) than for the CPI/r arm (115.8 years).
Efficacy End Points
Treatment response. Patients who received TPV/r demon-
strated a significantly higher treatment response rate (according
to intent-to-treat, noncompleter-considered-failure analysis),
compared with CPI/r recipients (41.5% vs. 22.3%; )P
! .0001
(figure 2A). After response rates for the 2 arms were adjusted
for different CPIs and enfuvirtide use, TPV/r had an 18.4%
higher treatment response rate, compared with CPI/r (95% CI,
11.4%–25.3%). When treatment response rate was analyzed by
the individual CPI, TPV/r was superior to each CPI (lopinavir
group, 37.2% for tipranavir vs. 24.1% for lopinavir [
P p
]; saquinavir group, 45.3% for tipranavir vs. 18.8% for
.0069
saquinavir [ ]; amprenavir group, 52.4% for tipran-
P p .0005
avir vs. 24.4% for amprenavir [ ]; and indinavir
P p .0057
group, 50.0% for tipranavir vs. 7.7% for indinavir [ ]).
P p .02
A superior treatment response was also reported with the
TPV/r group in patients with 3–4 or 5–6 primary PI-associated
mutations at week 24, compared with the CPI/r group (3–4
mutations, 78 [42.9%] of 182 patients vs. 30 [15.5%] of 194
patients; 5–6 mutations, 2 [66.7%] of 3 patients vs. 1 [33.3%]
of 3 patients). Furthermore, patients with 1–2 PI mutations at
codons 33, 82, 84, or 90 in the TPV/r group had greater treat-
ment response values than did comparable patients in the CPI/
r group (1 mutation, 42 [46.2%] of 91 patients vs. 25 [32.5%]
of 77 patients; 2 mutations, 81 [42.2%] of 192 patients vs. 36
[17.6%] of 204 patients). At week 24, when the treatment re-
sponse was evaluated in 182 TPV/r recipients with an available
baseline phenotype, there was a 47% response rate (54 of 115
patients) in patients with a baseline IC
50
fold-change of !3,
compared with 28% (19 of 67 patients) in those with a baseline
IC
50
fold-change of 3–8. Patients with a baseline HIV-1 load
of
!10,000 copies/mL were more likely to achieve a treatment
response than were those with higher baseline HIV-1 loads
(table 2).
Other efficacy end points. The 24-week mean reduction in
HIV-1 load from baseline was significantly greater in the TPV/
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
1340 • CID 2006:43 (15 November) • HIV/AIDS
Figure 1. Patient disposition in a study of the efficacy of the protease inhibitors tipranavir and ritonavir. CPI/r, ritonavir-boosted comparator protease
inhibitor; TPV/r, ritonavir-boosted tipranavir.
r group (⫺1.28 log
10
) than in the CPI/r group (⫺0.64 log
10
;
) (figure 2B). More TPV/r recipients achieved an un-
P
! .001
detectable HIV-1 load (cutoff of
!400 copies/mL, 34.7%; cutoff
of
!50 copies/mL, 25.1%), compared with CPI/r recipients
(cutoff of
!400 copies/mL, 16.5%; cutoff of !50 copies/mL,
10.0%; ) (figure 2C). Furthermore, among TPV/r and
P
! .0001
CPI/r recipients who received enfuvirtide, the proportion of
patients with an undetectable HIV-1 load increased during
treatment (for TPV/r recipients, 47.1% and 32.8% for cutoff
values of
!400 and !50 copies/mL, respectively; for CPI/r re-
cipients, 21.9% and 14.3% for cutoff values of
!400 and !50
copies/mL, respectively). The mean increase from baseline in
the CD4
+
cell count was significantly greater in the TPV/r group
than in the CPI/r group (+54 vs. +24 cells/mm
3
; ) (fig-
P
! .001
ure 2D).
The treatment response rate for TPV/r increased from 11.6%
(5 of 43 patients), when the optimized background regimen
contained no genotypically susceptible drugs, to 57.6% (19 of
33 patients), when there were ⭓3 genotypically susceptible
drugs. Response rates with CPI/r ranged from 13.2% (7 of 53
patients), when there were no genotypically active drugs, to
41.0% (16 of 39 patients), when there were
13 active drugs.
The addition of enfuvirtide to the optimized background reg-
imen improved treatment response, from 31.3% to 58.0% in
the TPV/r group and from 18.6% to 29.5% in the CPI/r group.
The effect of enfuvirtide on treatment response was enhanced
in TPV/r-treated patients who were enfuvirtide naive (66.7%),
compared with enfuvirtide-experienced patients (31.0%).
Trough plasma concentrations were analyzed at weeks 2 and
4. Detectable plasma PI concentrations had to be documented
before approval was granted for a switch of a patient from the
CPI/r group to the TPV/r group. There was no difference in
mean drug concentration measurements for patients who
changed treatment group versus those who did not.
Safety
All 620 treated patients were included in the safety analysis.
Most patients experienced at least 1 adverse event (90.7% of
TPV/r recipients and 86.4% of CPI/r recipients) (table 3). The
majority of adverse events in the 2 groups were graded as mild
(in 78.5% of TPV/r recipients and 75.7% of CPI/r recipients)
or moderate (in 59.8% of TPV/r recipients and 53.4% of CPI/
r recipients) in intensity. In the TPV/r group, adverse events
leading to discontinuation (⭓2 patients) were nausea, diarrhea,
increased alanine aminotransferase (ALT) levels, vomiting, cer-
ebrovascular accident, fatigue, pyrexia, and sepsis, whereas in
the CPI/r group, adverse events leading to discontinuation (⭓2
patients) were nausea, diarrhea, vomiting, and abdominal pain
(
!2% of patients in all cases).
Serious adverse events were experienced by 55 patients
(17.7%) in the TPV/r arm and 42 patients (13.6%) in the CPI/
r arm; fever (TPV/r group, 1.9%; CPI/r group, 1.3%), diarrhea
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
HIV/AIDS • CID 2006:43 (15 November) • 1341
Table 1. Baseline demographic characteristics of patients.
Characteristic
Treatment group
Overall
(n p 620)
TPV/r arm
(n p 311)
CPI/r arm
(n p 309)
Male sex 565 (91.1) 278 (89.4) 287 (92.9)
Age, median years (range) 44 (24 –80) 45 (24–80) 43 (28–70)
Median no. of NRTIs used (range) 6 (2–8) 6 (2–8) 6 (2–8)
Median no. of NNRTIs used (range) 2 (0–3) 2 (0–3) 1 (0–3)
Median no. of PIs used (range) 4 (1–7) 4 (1–7) 4 (1–7)
HIV-1 load, median log
10
copies/mL (range) 4.83 (2.01–6.31) 4.81 (2.34–6.13) 4.84 (2.01–6.31)
CD4
+
cell count, median cells/mm
3
(range) 123 (1–1184) 123 (1–860) 123 (1–1184)
Fusion inhibitor use 76 (12.3) 39 (12.5) 37 (12.0)
History of AIDS-defining illnesses 421 (67.9) 209 (67.2) 212 (68.6)
Median no. of primary protease mutations (range) 2.7 (0–5) 2.7 (0–5) 2.7 (0–5)
No. of protease mutations at 33, 82, 84, and 90
a
0 24 (3.9) 11 (3.5) 13 (4.2)
1 168 (27.1) 91 (29.3) 77 (24.9)
2 396 (63.9) 192 (61.7) 204 (66.0)
New PI selected that was not part of screening treatment regimen 359 (57.9) 176 (56.6) 183 (59.2)
Resistance to preselected PI
Susceptible
b
49 (7.9) 21 (6.8) 28 (9.1)
Possible resistance
c
214 (34.5) 120 (38.6) 94 (30.4)
Resistance
d
356 (57.4) 169 (54.3) 187 (60.5)
Median no. of genotypically available ARVs in the optimized back-
ground regimen (range)
e
1 (0–4) 2 (0–4) 1 (0–4)
Treatment assignment
Lopinavir 378 (61.0) 191 (61.4) 187 (60.5)
Indinavir 27 (4.4) 14 (4.5) 13 (4.2)
Saquinavir 128 (20.6) 64 (20.6) 64 (20.7)
Amprenavir 87 (14.0) 42 (13.5) 45 (14.6)
Enfuvirtide 224 (36.1) 119 (38.3) 105 (34.0)
Hepatitis virus coinfection status
HBsAg and HCV RNA negative 559 (90.2) 286 (92.0) 273 (88.3)
HBsAg positive and HCV RNA negative 26 (4.2) 14 (4.5) 12 (3.9)
HBsAg negative and HCV RNA positive 31 (5.0) 10 (3.2) 21 (6.8)
HBsAg and HCV RNA positive 2 (0.3) 0 2 (0.6)
Missing 2 (0.3) 1 (0.3) 1 (0.3)
Hepatitis B antibody positive 335 (54.0) 171 (55.0) 164 (53.1)
NOTE. Data are no. (%) of subjects, unless otherwise indicated. ARV, antiretroviral; CPI/r, ritonavir-boosted comparator protease inhibitor;
HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI: nucleoside reverse-
transcriptase inhibitor; TPV/r, ritonavir-boosted tipranavir.
a
Individual codons were counted, not multiple polymorphisms. Mixture of wild-type and mutant are counted as mutants. V3I was not counted.
b
No evidence of resistance detected using the HIV-1 genotyping method, versions 6.0 and 7.0 (TruGene).
c
Possible resistance detected using the HIV-1 genotyping method, versions 6.0 and 7.0 (TruGene).
d
Resistance detected using the HIV-1 genotyping method, versions 6.0 and 7.0 (TruGene).
e
Found to be susceptible or possibly resistant (excluding the study PI) by the HIV-1 genotyping method, versions 6.0 and 7.0 (TruGene);
enfuvirtide was always considered to be susceptible.
(TPV/r group, 1.6%; CPI/r group, 1.0%), and pneumonia
(TPV/r group, 1.6%; CPI/r group, 0.6%) were the most com-
mon adverse events. Severe adverse events (grade 3 or 4 ac-
cording to the Division of AIDS scoring system) were reported
for 71 patients (22.8%) in the TPV/r arm and 56 patients
(18.1%) in the CPI/r arm.
During the study, 15 types of AIDS-defining illnesses were
acquired by 11 patients (3.5%) in the TPV/r group and 16
patients (5.2%) in the CPI/r group. There was a higher fre-
quency of esophageal candidiasis in the CPI/r group (2.3% vs.
0.3%) and of wasting syndrome in the TPV/r group (1.0% vs.
0%). No other AIDS-defining illnesses were experienced by
12
patients in either group.
Laboratory abnormalities were generally more common in
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
1342 • CID 2006:43 (15 November) • HIV/AIDS
Figure 2. Comparison of virologic and immunologic responses in the ritonavir-boosted tipranavir (TPV/r) and ritonavir-boosted comparator protease
inhibitor (CPI/r) groups over 24 weeks. A, Treatment response (defined as a confirmed ⭓1-log
10
reduction in the HIV-1 load). B, HIV-1 load reduction.
C, Virologic response (defined as an HIV-1 load
!50 copies/mL). D, CD4
+
cell count. For the TPV/r group, all 311 patients were analyzed for all variables
except for the CD4
+
cell count, for which 1 data point was missing ( ). All 309 patients in the CPI/r arm were analyzed for all 4 responsen p 310
variables.
the TPV/r arm than in the CPI/r arm (table 2); most of these
were mild or moderate and asymptomatic. Elevations in hepatic
enzyme and plasma lipid levels were the most common grade
3 or 4 laboratory abnormalities reported. Among patients who
experienced elevations in the ALT level, 15 (9.0%) were coin-
fected with hepatitis B or C virus, whereas 6 (4.4%) were not.
Among patients who experienced elevated aspartate amino-
transferase levels, 11 (6.6%) were coinfected with hepatitis B
or C virus, and 3 (2.2%) were not. Seventeen of 21 TPV/r
recipients with grade 3 or 4 liver function test results continued
to received treatment without permanent discontinuation.
No patient with grade 3 or 4 elevated ALT or AST levels in
either group developed treatment-onset hepatitis or related he-
patic events. Some patients were concomitantly receiving po-
tentially hepatotoxic drugs (13 [54.2%] of the 24 TPV/r-treated
patients and 5 [62.5%] of the 8 CPI/r-treated patients with
elevated ALT or AST levels).
There were 8 deaths (2.6%) in the TPV/r arm and 6 deaths
(1.9%) in the CPI/r arm (6.0 and 5.2 deaths per 100 patient-
exposure-years, respectively). None were judged to be related
to treatment.
DISCUSSION
The results of this 24-week interim analysis demonstrate that,
when TPV/r is used as part of antiretroviral combination ther-
apy, it significantly suppresses viral replication and increases
CD4
+
cell counts in genotypically screened, highly antiretro-
viral-treatment experienced patients with multidrug-resistant
HIV-1 infection. A significantly greater proportion of patients
randomized to receive TPV/r (41.5%), compared with CPI/r
(22.3%), achieved an HIV-1 load reduction of ⭓1log
10
after
24 weeks. In addition, patients in the TPV/r group experienced
a significantly greater increase in CD4
+
cell counts than did
those in the CPI/r group, although small imbalances in baseline
characteristics may impact these results. These findings are im-
portant, because changes of this magnitude in virologic and
immunologic markers have been associated with a decreased
incidence of AIDS-defining events [29–32]. Furthermore, the
level of suppression of HIV-1 replication observed at 24 weeks
was comparable with that reported in the T-20 versus Opti-
mized Regimen Only (TORO) trials of treatment-experienced
patients, in which patients were randomized to receive enfu-
virtide or an optimized background regimen alone [33, 34].
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
HIV/AIDS • CID 2006:43 (15 November) • 1343
Table 2. Patients with a treatment response at week 24, according to baseline HIV-1
load.
Characteristic
Treatment group, no. of responders/
no. of evaluable patients (%)
Overall population TPV/r arm CPI/r arm
Total treated patients 198/620 (31.9) 129/311 (41.5) 69/309 (22.3)
Baseline HIV RNA level, copies/mL
!1000 1/4 (25.0) 1/3 (33.3) 0/1 (0)
1000–10,000 40/93 (43.0) 24/45 (53.3) 16/48 (33.3)
110,000 to 100,000 87/265 (32.8) 58/134 (43.3) 29/131 (22.1)
1100,000 70/258 (27.1) 46/129 (35.7) 24/129 (18.6)
NOTE. CPI/r, ritonavir-boosted comparator protease inhibitor; TPV/r, ritonavir-boosted tipranavir.
One treatment aim for patients with prior antiretroviral ex-
posure and drug resistance is to reestablish maximum virologic
suppression, and current guidelines recommend the addition
of a newer PI boosted with ritonavir, with or without enfu-
virtide, to a standard treatment regimen [35]. The results of
the RESIST-1 trial demonstrated that increasing the number of
background antiretroviral agents to which patients’ isolates
were susceptible enhanced the treatment response among both
TPV/r recipients and CPI/r recipients. This was true for the
TPV/r group when enfuvirtide, for which no level of cross-
resistance was expected, was added; the proportion of treatment
responders also increased (but less so) in the CPI/r arm. For
TPV/r recipients who were enfuvirtide naive, the inclusion of
enfuvirtide further enhanced the treatment response, compared
with that of patients who had a history of prior enfuvirtide
use. Similarly, having additional drugs beyond enfuvirtide in
the optimized background regimen to which patients’ isolates
were susceptible increased the proportion of treatment
responders.
Overall tolerability and the occurrence of adverse events were
comparable between treatment arms. Most adverse events were
mild or moderate in severity and were usually observed after
administration of boosted PIs in a population with advanced
immunodeficiency [36, 37]. Diarrhea, nausea, and fatigue were
the most frequently occurring adverse events reported in both
groups.
The grade 3 or 4 laboratory abnormalities observed in both
treatment groups were similar, although some occurred more
frequently in the TPV/r arm; asymptomatic elevations in ALT
and AST levels and increases in triglyceride and cholesterol
levels were more common among TPV/r recipients. Despite
these abnormalities, most patients continued to receive TPV/r
therapy. As seen with other boosted PIs, coinfection with hep-
atitis B or C virus and elevated transaminase levels at baseline
increased the risk of elevated ALT or AST levels during treat-
ment. Moreover, elevations in triglyceride levels were more
common among patients who had high triglyceride values at
baseline. One possible explanation for the observed increase in
liver events and in triglyceride levels is the higher total daily
dose of ritonavir used in TPV/r-treated patients (400 mg per
day). Average ritonavir trough concentrations are lower in pa-
tients receiving TPV/r than in those who receive some other
PIs (e.g., lopinavir and saquinavir) plus an optimized back-
ground regimen [38]; therefore, a higher daily dose of ritonavir
was used in tipranavir-treated patients in this study.
Because the trial was open label, investigators may have been
more prone to report adverse events for the investigational drug
than for approved agents [39]. More importantly, CPI/r-treated
patients were given the option of discontinuing treatment after
8 weeks in the event of a lack of initial virologic response or
confirmed virologic failure, to join a TPV/r rollover study. Be-
fore week 24, a total of 33.0% of CPI/r recipients opted to
discontinue receiving the study medication for these reasons,
and most of these patients joined the rollover study. This led
to a substantially longer treatment exposure among TPV/r re-
cipients than among CPI/r recipients. This greater exposure
may have led to an accumulation of adverse events (related or
unrelated to the study drug) in the TPV/r arm.
In conclusion, the combination of TPV/r with an active op-
timized background regimen in antiretroviral-experienced pa-
tients resulted in significant improvements in virologic and
immunologic responses through 24 weeks, compared with CPI/
r and an optimized background regimen. This would suggest
that TPV/r (500 mg/200 mg twice per day), as part of com-
bination antiretroviral therapy, plays an important role in the
achievement of effective viral suppression in patients infected
with multidrug-resistant strains who have limited treatment
options. The results of the 48-week analysis will determine the
durability of TPV/r in achieving and maintaining effective viral
suppression in this important patient population.
RESIST-1 STUDY GROUP
The resistance panel consisted of J. Baxter (Cooper Hospital,
Camden, NJ), C. A. Boucher (University of Utrecht, Utrecht,
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
1344 • CID 2006:43 (15 November) • HIV/AIDS
Table 3. Adverse events (related or not related to treatment; grade 1–4) and laboratory
abnormalities (grade 3–4 ) noted among study subjects.
Characteristic
Treatment group
Overall population
(n p 620)
TPV/r arm
(n p 311)
CPI/r arm
(n p 309)
Adverse event
Any
a
549 (88.5) 282 (90.7) 267 (86.4)
Diarrhea 144 (23.2) 75 (24.1) 69 (22.3)
Nausea 131 (21.1) 64 (20.6) 67 (21.7)
Fatigue 96 (15.5) 47 (15.1) 49 (15.9)
Headache 65 (10.5) 37 (11.9) 28 (9.1)
Vomiting 57 (9.2) 32 (10.3) 25 (8.1)
Pyrexia 53 (8.5) 29 (9.3) 24 (7.8)
Upper respiratory tract infection 45 (7.3) 24 (7.7) 21 (6.8)
Injection site reaction 51 (8.2) 22 (7.1) 29 (9.4)
Grade 3 or 4 laboratory abnormalities
Total no. of subjects 608 304 304
Elevated alanine aminotransferase level 25 (4.1) 21 (6.9) 4 (1.3)
Elevated aspartate aminotransferase level 19 (3.1) 14 (4.6) 5 (1.6)
Elevated amylase level 43 (7.0) 21 (6.9) 22 (7.2)
Elevated lipase level 14 (2.3) 9 (2.9) 5 (1.6)
Elevated cholesterol level 13 (2.1) 13 (4.2) 0
Elevated triglyceride level 104 (17.1) 66 (21.7) 38 (12.5)
Increased glucose level 11 (1.8) 6 (2.0) 5 (1.6)
NOTE. Data are no. (%) of subjects. CPI/r, ritonavir-boosted comparator protease inhibitor; TPV/r, rito-
navir-boosted tipranavir.
a
Averse events were observed in 15% of patients and were treatment related or not treatment related.
The Netherlands), and J. M. Schapiro (Stanford University,
Stanford, CA).
In addition to the listed authors, the RESIST-1 study group
included the following institutions and persons: B. Akil (Health
Innovations Research, Los Angeles, CA); M. Goldman, H. Kat-
ner, and F. C. Smail (University of Tennessee at Memphis); D.
Barker (CORE Center, Chicago, IL); W. Mazur (Early Inter-
vention Program [EIP] Clinic, Camden, NJ); S. Becker (Pacific
Horizon Medical Group, San Francisco, CA); K. Peterson (Na-
tional Naval Medical Center, Bethesda, MD); G. Blick (Circle
Medical, LLC, Norwalk, CT); C. Borkert (East Bay AIDS Center,
Berkeley, CA); A. Burnside (Burnside Clinic, Columbia, SC);
P. Cimoch (Orange County Center for Special Immunology,
Fountain Valley, CA); A. Collier (University of Washington
Harborview Medical Center, Seattle); E. DeJesus (IDC Research
Initiative, Altamonte Springs, FL); R. Eng (Veteran’s Affairs
New Jersey Health Care System, East Orange, NJ); J. Ernst
(AIDS Community Research Initiative of America [ACRIA],
New York); C. Farthing (AHF Research Center, Los Angeles);
J. Feinberg (University of Cincinnati Medical Center, Cincin-
nati, OH); J. Fessel (San Antonio Infectious Diseases Consult-
ants, San Antonio, TX); I. Frank (University of Pennsylvania
Medical Center, Division of Infectious Disease, Philadelphia);
M. Frank (Froedtert Memorial Lutheran Hospital, Milwaukee,
WI); J. Gallant (John Hopkins University School of Medicine,
Baltimore, MD); J. Gathe (Therapeutic Concepts, Houston,
TX); M. Goldman (Indiana University Hospital, Indianapolis);
R. Greenberg (University of Kentucky Medical Center, Lexing-
ton); P. Greiger-Zanlungo (Mount Vernon Hospital, Mount
Vernon, NY); B. Gripshove (University Hospitals of Cleveland,
Cleveland, OH); H. Grossman (Pollari Medical Group, New
York); T. Hawkins (Southwest CARE Center, Sante Fe, NM);
J. Hellinger (Community Research Initiative of New England,
Boston, MA); C. Hicks (Duke University Medical Center, Dur-
ham, NC); H. Horowitz (Westchester Medical Center, Valhalla,
NY); A. Huang (University of Louisville, Louisville, KY); D.
Jayaweera (Jackson Medical Tower, Miami, FL); J. Jemsek (Jem-
sek Clinic, Huntersville, NC); H. Katner (Mercer University
School of Medicine, Macon, GA); J. Fraiz (Infectious Disease
of Indiana, Indianapolis); H. Kessler (Rush-Presbyterian-St.
Luke’s Medical Center, Chicago); J. Kostman (Cecile Gallo,
Philadelphia FIGHT, Philadelphia, PA); A. Labriola (Washing-
ton VAMC, Washington); H. Lampiris (San Francisco VA Med-
ical Center, San Francisco); R. MacArthur (University Health
Center, San Francisco); D. Margolis (Dallas VAMC, Dallas); N.
Markowitz (Henry Ford Hospital, Detroit, MI); D. Mildvan
(Beth Israel Medical Center, New York); S. Miles (Clinical Re-
search Puerto Rico, Santurce, PR); A. Morris (Community Re-
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
HIV/AIDS • CID 2006:43 (15 November) • 1345
search Initiative of New England, Springfield, MA); R. A. Myers
(Phoenix Body Positive, Phoenix, AZ); J. Nadler (Hillsborough
County Health Dept., Tampa, FL); G. Pierone (Treasure Coast
Infectious Disease Consultants, Vero Beach, FL); G. Drusano
(Albany Medical College, Albany, NY); D. Rimland (Atlanta
VA Medical Ctr, Decatur, GA); M. Rodriguez (Houston Vet-
eran’s Administration, Houston); S. Santiago (CARES Re-
source, Miami); S. Schneider (Living Hope Clinical Trials, Long
Beach, CA); R. Schwartz (Associates In Research, Fort Myers,
FL); D. Norris (Comprehensive Research, Tampa); M. Sension
(North Broward Hospital District, Fort Lauderdale, FL); L. Sla-
ter (Infect Disease Inst. Clinical Trials Unit, Oklahoma City);
R. Smith (AIDS Consortium Service, Portland, ME); K. Squires
(University of Southern California/LA County USC Medical
Center, Los Angeles); R. Steigbigel (University of New York at
Stony Brook, Stony Brook); C. Steinhart (Steinhart Medical
Associates, Miami); R. Groger (Washington University AIDS
Clinical Trial Unit, St. Louis, MO); M. Thompson (AIDS Re-
search Consortium of Atlanta, Atlanta); F. Torriani (University
of California, San Diego, San Diego); V. Vega (Infectious Dis-
ease Associates, Sarasota, FL); D. Wheeler (Infectious Disease
Physicians Research, Annandale, VA); M. Wohlfeiler (Wohl-
feiler, Piperato & King, MD, Miami); B. Yangco (Infectious
Disease Research Institute, Tampa); J. Zachary (HIV Outpatient
Program [HOP], New Orleans, LO); T. Wilkin (The Cornell
HIV Clinical Trials Unit, New York); W. D. Hardy (Cedars-
Sinai Medical Center, Los Angeles); M. Wallace (Naval Medical
Center, San Diego, CA); D. Kuritzkes (Brigham Women’s Hos-
pital, Boston); R. Gandhi (Massachusettes General Hospital,
Boston); D. Ward (Dupont Circle Physicians Group, Washing-
ton); D. Berger (Northstar Medical, Chicago); D. Brand (North
Texas Center for AIDS and Clinical Research, Dallas); R. Corales
(Community Health Network, Rochester); T. File (Summa
Health System, HIV C.A.R.E. Center, Akron, OH); L. Tkatch
(Pinnacle Health, Harrisburg, PA); P. Bellman (The Office of
Dr. Paul Bellman, New York); H. Albrecht (Infectious Diseases
Clinics of Emory, Atlanta); D. Cooper (St. Vincents Hospital,
Darlinghurst, NSW, Australia); J. Gold (Albion Street Clinic,
Surry Hills, New South Wales [NSW]); J. Hoy (Alfred Hospital,
Melbourne, Victoria, Australia); C. Workman (Ground Zero,
Darlinghurst, NSW); J. Chuah (Gold Coast Sexual Health
Clinic, Miami, Queensland); M. Bloch (Holdsworth House
General Practice, Darlinghurst, NSW); D. Baker; W Cameron
(The Ottawa Hospital, Ottawa); B. Conway (Downtown In-
fectious Diseases Clinic, Vancouver, BC); P. Cote (Clinique
Medicale Du Quartier Latin, Montreal, QC); F. Crouzat (Ca-
nadian Immunodeficiency Research Collaborative Inc., To-
ronto, ON); K. Gough (St. Michael’s Hospital, Toronto, ON);
R Lalonde (Montreal Chest Institute, Montreal); A. Rachlis
(Sunnybrook & Women’s College Health Centre, Toronto, ON);
S. Rosser (St. Boniface General Hospital, Winnipeg, MB); F.
Smaill (McMaster University Medical Centre, Hamilton, ON);
B. Trottier (Clinique medicale l’Actuel, Montreal); S. Walmsley
(Toronto General Hospital, Toronto); C. Tsoukas (Montreal
General Hospital, McGill University Health Centre, Montreal);
L. Johnston (Centre For Clinical Research, Halifax, NOVA
SCO)
Acknowledgments
Financial support. Boehringer Ingelheim Pharmaceuticals.
Potential conflicts of interest. D.A.C. is a member of the speakers’
bureau for Boehringer Ingelheim GmbH. C.F. has received research study
grants from Boehringer Ingelheim and Abbott and is a member of the
speakers’ bureau and an advisory board participant for Boehringer Ingel-
heim and Abbott. D.J. is a consultant and member of the speakers’ bureau
for GlaxoSmithKline, Bristol-Myers Squibb, Roche, Johnson & Johnson,
Abbott, Boehringer Ingelheim GmbH, Virco, and Gilead and has received
research grants from GlaxoSmithKline, Bristol-Myers Squibb, Johnson &
Johnson, and Roche. G.P. has received research and educational grants
from Boehringer Ingelheim and is a member of the speakers’ bureau for
Boehringer Ingelheim GmbH. C.R.S. has served as an advisor for Boeh-
ringer Ingelheim. B.T. has been a member of the speakers’ bureau and an
advisory board participant for Boehringer Ingelheim GmbH. S.L.W. has
served as a consultant, on advisory boards, on speaker bureaus, and in the
conduct of clinical trials with Boehringer Ingelheim, Roche, Abbott, Bristol-
Myers Squibb GmbH, GlaxoSmithKline, Gilead, Tibotec, Merck, Pfizer,
and Agouron. C.W. has served as a consultant on advisory boards for Merck
Sharp & Dohme, Abbott, Roche, and Jansen-Cilag; has received honoraria
from Abbott, Roche, Jansen-Cilag, Gilead, and Merck Sharp & Dohme;
and has received grants from Abbott, Merck Sharp & Dohme, Roche,
Jansen-Cilag, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, and Novar-
tis. G.M., V.K., C.D., S.M., D.M., and D.N. are all employees of Boehringer
Ingelheim. J.G. and D.N.: no conflicts.
References
1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity
and mortality among patients with advanced human immunodefi-
ciency virus infection. HIV Outpatient Study Investigators. N Engl J
Med 1998; 338:853–60.
2. Cingolani A, Antinori A, Rizzo MG, et al. Usefulness of monitoring
HIV drug resistance and adherence in individuals failing highly active
antiretroviral therapy: a randomized study (ARGENTA). AIDS 2002;
16:369–79.
3. Wit FW, van Leeuwen R, Weverling GJ, et al. Outcome and predictors
of failure of highly active antiretroviral therapy: one-year follow-up of
a cohort of human immunodeficiency virus type 1-infected persons.
J Infect Dis 1999; 179:790–8.
4. Deeks SG. Determinants of virological response to antiretroviral ther-
apy: implications for long-term strategies. Clin Infect Dis 2000;
30(Suppl 2):S177–84.
5. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and
virological failure on highly active antiretroviral therapy in HIV-1 pa-
tients: a prospective cohort study. Swiss HIV Cohort Study. Lancet
1999; 353:863–8.
6. Dieleman JP, Jambroes M, Gyssens IC, et al. Determinants of recurrent
toxicity-driven switches of highly active antiretroviral therapy. The
ATHENA cohort. AIDS 2002; 16:737–45.
7. Raboud JM, Harris M, Rae S, Montaner JS. Impact of adherence on
duration of virological suppression among patients receiving combi-
nation antiretroviral therapy. HIV Med 2002; 3:118–24.
8. Condra JH, Petropoulos CJ, Ziermann R, Schleif WA, Shivaprakash
M, Emini EA. Drug resistance and predicted virologic responses to
human immunodeficiency virus type 1 protease inhibitor therapy. J
Infect Dis 2000; 182:758–65.
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
1346 • CID 2006:43 (15 November) • HIV/AIDS
9. Hertogs K, Bloor S, Kemp SD, et al. Phenotypic and genotypic analysis
of clinical HIV-1 isolates reveals extensive protease inhibitor cross-
resistance: a survey of over 6000 samples. AIDS 2000; 14:1203–10.
10. Van Vaerenbergh K, Van Laethem K, Albert J, et al. Prevalence and
characteristics of multinucleoside-resistant human immunodeficiency
virus type 1 among European patients receiving combinations of nu-
cleoside analogues. Antimicrob Agents Chemother 2000; 44:2109–17.
11. Johnson VA, Brun-Vezinet F, Clotet B, et al. Drug resistance mutations
in HIV-1. Top HIV Med 2003; 11:215–21.
12. Lundgren JD, Ledergerber B, Fusco GP, et al. Risk of death following
triple class virological failure: the PLATO collaboration [abstract H-
450]. In: Program and abstracts of the 43rd Interscience Conference
on Antimicrobial Agents and Chemotherapy (Chicago). Washington,
DC: American Society for Microbiology, 2003.
13. Chrusciel RA, Strohbach JW. Non-peptidic HIV protease inhibitors.
Curr Top Med Chem 2004; 4:1097–114.
14. Mehandru S, Markowitz M. Tipranavir: a novel non-peptidic protease
inhibitor for the treatment of HIV infection. Expert Opin Investig
Drugs 2003; 12:1821–8.
15. Randolph JT, DeGoey DA. Peptidomimetic inhibitors of HIV protease.
Curr Top Med Chem 2004; 4:1079–95.
16. Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly pro-
tease inhibitor-resistant HIV-1 clinical samples. AIDS 2000; 14:1943–8.
17. Poppe SM, Slade DE, Chong KT, et al. Antiviral activity of the dihy-
dropyrone PNU-140690, a new nonpeptidic human immunodeficiency
virus protease inhibitor. Antimicrob Agents Chemother 1997; 41:
1058–63.
18. Back NK, van Wijk A, Remmerswaal D, et al. In-vitro tipranavir sus-
ceptibility of HIV-1 isolates with reduced susceptibility to other pro-
tease inhibitors. AIDS 2000; 14:101–2.
19. Khaliq Y, Gallicano K, Tisdale C, Carignan G, Cooper C, McCarthy
A. Pharmacokinetic interaction between mefloquine and ritonavir in
healthy volunteers. Br J Clin Pharmacol 2001; 51:591–600.
20. Koudriakova T, Iatsimirskaia E, Utkin I, Gangl E, Vouros P, Storozhuk
E. Metabolism of the human immunodeficiency virus protease inhib-
itors indinavir and ritonavir by human intestinal microsomes and ex-
pressed cytochrome P4503A4/3A5: mechanism-based inactivation of
cytochrome P4503A by ritonavir. Drug Metab Dispos 1998; 26:552–61.
21. Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D. Potent
inhibition of the cytochrome P-450 3A-mediated human liver micro-
somal metabolism of a novel HIV protease inhibitor by ritonavir: a
positive drug-drug interaction. Drug Metab Dispos 1999; 27:902–8.
22. Tredger JM, Stoll S. Cytochromes P450-their impact on drug devel-
opment. Hospital Pharmacist 2002; 9:167–73.
23. MacGregor TR, Sabo JP, Norris SH, Johnson P, Galitz L, McCallister
S. Pharmacokinetic characterization of different dose combinations of
coadministered tipranavir and ritonavir in healthy volunteers. HIV Clin
Trials 2004; 5:371–82.
24. McCallister S, Valdez H, Curry K, et al. A 14-day dose-response study
of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease
inhibitor tipranavir in treatment-naive HIV-1-infected patients. J Ac-
quir Immune Defic Syndr 2004; 35:376–82.
25. Cooper D, Hicks C, Cahn P, et al. 24-week RESIST study analyses: the
efficacy of tipranavir/ritonavir is superior to lopinavir/ritonavir, and
the TPV/r treatment response is enhanced by inclusion of genotypically
active antiretrovirals in the optimized background regimen [abstract
560]. In: Program and abstracts of the 12th Conference on Retroviruses
and Opportunistic Infections (Denver). Alexandria, VA: Foundation
for Retrovirology and Human Health, 2006.
26. Cahn P, Villacian J, Lazzarin A, et al. Ritonavir-boosted tipranavir
demonstrates superior efficacy to ritonavir-boosted protease inhibitors
in treatment-experienced HIV-infected patients: 24-week results of the
RESIST-2 trial. Clin Infect Dis 2006; 43:1347–56 (in this issue).
27. Ledergerber B, Lundgren JD, Walker AS, et al. Predictors of trend in
CD4-positive T-cell count and mortality among HIV-1-infected in-
dividuals with virological failure to all three antiretroviral-drug classes.
Lancet 2004; 364:51–62.
28. Cochran WG. Some methods for strengthening the common x
2
tests.
Biometrics 1954; 10:417–51.
29. O’Brien WA, Hartigan PM, Daar ES, Simberkoff MS, Hamilton JD.
Changes in plasma HIV RNA levels and CD4
+
lymphocyte counts
predict both response to antiretroviral therapy and therapeutic failure.
VA Cooperative Study Group on AIDS. Ann Intern Med 1997; 126:
939–45.
30. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley
LA. Prognosis in HIV-1 infection predicted by the quantity of virus
in plasma. Science 1996; 272:1167–70.
31. Human immunodeficiency virus type 1 RNA level and CD4 count as
prognostic markers and surrogate end points: a meta-analysis. HIV
Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses
2000; 16:1123–33.
32. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-
controlled trial of ritonavir in advanced HIV-1 disease. The Advanced
HIV Disease Ritonavir Study Group. Lancet 1998; 351:543–9.
33. Lalezari JP, Henry K, O’Hearn M, et al. Enfuvirtide, an HIV-1 fusion
inhibitor, for drug-resistant HIV infection in North and South America.
N Engl J Med 2003; 348:2175–85.
34. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients
infected with drug-resistant HIV-1 in Europe and Australia. N Engl J
Med 2003; 348:2186–95.
35. DHHS Panel on Antiretroviral Guidelines for Adults and Adoles-
cents–A Working Group of the Office of AIDS Research Advisory
Council (OARAC). Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Available at: http://aidsinfo
.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 26 May
2006.
36. Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine
and lamivudine for the treatment of antiretroviral-naive adults with
HIV-1 infection: 48-week results. AIDS 2001; 15:F1–9.
37. Pulido F, Katlama C, Marquez M, et al. A randomized study investi-
gating the efficacy and safety of amprenavir in combination with low-
dose ritonavir in protease inhibitor-experienced HIV-infected adults.
HIV Med 2004; 5:296–302.
38. Sabo JP, Piliero PJ, Lawton A, MacGregor TR, Leith J. A comparison
of steady-state trough plasma ritonavir concentrations for HIV+ pa-
tients receiving an optimized background regimen and ritonavir-
boosted tipranavir (TPV/r), lopinavir (LPV/r), saquinavir (SQV/r) or
amprenavir (APV/r) [poster 43]. In: Proceedings of the 7th Interna-
tional Workshop on Clinical Pharmacology of HIV Therapy (Lisbon).
Utrecht, The Netherlands: Virology Education, 2006.
39. Moore N, Hall G, Sturkenboom M, Mann R, Lagnaoui R, Begaud B.
Biases affecting the proportional reporting ratio (PPR) in spontaneous
reports pharmacovigilance databases: the example of sertindole. Phar-
macoepidemiol Drug Saf 2003; 12:271–81.
by guest on December 28, 2015http://cid.oxfordjournals.org/Downloaded from
