Tipranavir/Ritonavir (500/200 mg and 500/100 mg) Was Virologically Non-Inferior to Lopinavir/Ritonavir (400/100 mg) at Week 48 in Treatment-Naïve HIV-1-Infected Patients: A Randomized, Multinational, Multicenter Trial
Tipranavir/Ritonavir (500/200 mg and 500/100 mg) Was Virologically Non-Inferior to Lopinavir/Ritonavir (400/100 mg) at Week 48 in Treatment-Naïve HIV-1-Infected Patients: A Randomized, Multinational, Multicenter Trial
David A. Cooper 0 1 2
Damien V. Cordery 0 1 2
Roberto Zajdenverg 0 1 2
Kiat Ruxrungtham 0 1 2
Keikawus Arastéh 0 1 2
Frank Bergmann 0 1 2
José L. de Andrade Neto 0 1 2
Joseph Scherer 0 1 2
Ricardo L. Chaves 0 1 2
Patrick Robinson 0 1 2
study team 0 1 2 3
0 Current address: Novartis Pharma AG. Department:Global Medical Affairs , Basel , Switzerland
1 1 The Kirby Institute, University of New South Wales , Sydney , Australia , 2 Head of Medical Affairs, HIV, Infectious Diseases and Immuneinflammatory Diseases , GlaxoSmithKline, Rio de Janeiro, Brazil, 3 HIV- NAT , Thai Red Cross AIDS Research Centre; and Faculty of Medicine, Chulalongkorn University , Bangkok, Thailand, 4 Epimed GmbH , Vivantes Auguste-Viktoria Hospital , Berlin, Germany , 5 Department of Internal Medicine, Infectiology and Pulmonology, Humboldt University , Berlin, Germany , 6 Instituto A Z de Pesquisa E Ensino, Pesquisa E Ensino, Brazil, 7 Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield, CT , United States of America, 8 Boehringer Ingelheim GmbH , Ingelheim , Germany
2 Editor: Alan Landay, Rush University , UNITED STATES
3 Membership of the study team is listed in the Acknowledgments
Ritonavir-boosted tipranavir (TPV/r) was evaluated as initial therapy in treatment-naïve HIV-1-infected patients because of its potency, unique resistance profile, and high genetic barrier. Trial 1182.33, an open-label, randomized trial, compared two TPV/r dose combinations versus ritonavir-boosted lopinavir (LPV/r). Eligible adults, who had no prior antiretroviral therapy were randomized to twice daily (BID) 500/100 mg TPV/r, 500/200 mg TPV/r, or 400/100 mg LPV/r. Each treatment group also received Tenofovir 300 mg + Lamivudine 300 mg QD. The primary endpoint was a confirmed viral load (VL) <50 copies/mL at week 48 without prior antiretroviral regimen changes. Primary analyses examined CD4adjusted response rates for non-inferiority, using a 15% non-inferiority margin. At week 48, VL<50 copies/mL was 68.4%, 69.9%, and 72.4% in TPV/r100, TPV/r200, and LPV/r groups, respectively, and TPV/r groups showed non-inferiority to LPV/r. Discontinuation due to adverse events was higher in TPV/r100 (10.3%) and TPV/r200 (15.3%) recipients versus
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: This study was funded by
BoehringerIngelheim. Author Joseph Scherer is employed by
Boehringer-Ingelheim. Patrick Robinson was formerly
employed by Boehringer-Ingelheim during the
planning, conduct analysis, and manuscript
preparation. Ricardo L. Chaves was employed by
Boehringer-Ingelheim during the course of the study.
Boehringer-Ingelheim played a role in study design,
LPV/r (3.2%) recipients. The frequency of grade
3 transaminase elevations was higher in
the TPV/r200 group than the other groups, leading to closure of this group. However, upon
continued treatment or following re-introduction after treatment interruption, transaminase
elevations returned to grade
2 in >65% of patients receiving either TPV/r200 or TPV/r100.
The trial was subsequently discontinued; primary objectives were achieved and continuing
data collection, analysis, preparation of the
manuscript, and decision to publish. Roberto
Zajdenverg is employed by GlaxoSmithKline.
GlaxoSmithKline provided support in the form of
salary for author RZ, but did not have any additional
role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
The specific role of this author is articulated in the
‘author contributions’ section. GlaxoSmithKline was
the source of the background ARV medication, but
played no additional role in the study.
Competing Interests: This study was funded by
Boehringer-Ingelheim. Joseph Scherer is currently an
employee of Boehringer-Ingelheim Pharmaceuticals,
Inc. Patrick Robinson was an employee of
Boehringer-Ingelheim during the conduct of the study
and the preparation of the manuscript. Ricardo
Chaves was formerly employed with
BoehringerIngelheim Pharmaceuticals, Inc. Roberto Zajdenverg
is employed at GlaxoSmithKline, Brazil. Kiat
Ruxrungtham has served as a consultant for Merck,
Tibotec, and Mylan. He has been paid for speaking
engagements with Bristol-Myers Squibb, Merck,
Roche, Jensen-Cilag, GlaxoSmithKline, Thai GPO,
and Mylan Lab limited. Keikawus Arastéh was
speaker, investigator, and advisor as well as
countrycoordinating investigator (Tranxition study) for
Boehringer-Ingelheim Pharmaceuticals, Inc. Frank
Bergmann has received support for travel to meetings
for the study by Boehringer-Ingelheim
Pharmaceuticals, Inc. There are no patents, products
in development, or marketed products to declare.
This does not alter the authors' adherence to all the
PLOS ONE policies on sharing data and materials.
Abbreviations: ARVs, antiretroviral drugs; ALT,
alanine aminotransferase; AST, aspartate
aminotransferase; cART, combination antiretroviral
therapy; CPI/r, comparator protease inhibitor; CDC,
Centers for Disease Control; DAIDS, Division of
AIDS; LPV/r, ritonavir-boosted lopinavir; 3TC,
lamivudine; NtRTI, nucleotide reverse transcriptase
inhibitor; NRTI, nucleoside reverse transcriptase
inhibitor; NNRTI, non-nucleoside reverse
transcriptase inhibitor; NCF, non-completers
considered failures; OBR, optimized backbone
regimen; PI, protease inhibitor; RTV, ritonavir; TPV/r,
ritonavir-boosted tipranavir; TDF, tenofovir disoproxil
fumarate; TTF, time to treatment failure; VL, viral
TPV/r100 was less tolerable than standard of care for initial highly active antiretroviral ther
apy. All treatment groups had similar 48-week treatment responses. TPV/r100 and TPV/
r200 regimens resulted in sustained treatment responses, which were non-inferior to LPV/r
at 48 weeks. When compared with the LPV/r regimen and examined in the light of more
current regimens, these TPV/r regimens do not appear to be the best options for
treatmentnaïve patients based on their safety profiles.
In the mid 2000s, there were few options available for patients infected with HIV multi
resistant to protease inhibitor (PI) antiretroviral drugs (ARVs). During the course of tipranavir’s
(TPV) development for treatment of patients with resistant HIV, substantial efficacy was
]. Based on therapies available at the time, approximately 50% of patients
receiving first-line therapy would fail by 1 year, chiefly because of emerging resistance . It was
hypothesized that first-line treatment with TPV could achieve useful efficacy and might
prevent the emergence of PI resistance, because of a high genetic barrier to the emergence of
resistance. Therefore, this trial was undertaken in 2004–2006 with the aspiration of avoiding
emergence of ARV resistance during first-line therapy.
Combination antiretroviral therapy (cART) has significantly advanced HIV-1 treatment
over the past decade, and first-line therapy regimens have become much more effective in
achieving and maintaining long-term virologic suppression of plasma HIV RNA [
However, emergence of resistance remains a concern [
4, 11, 12
]. Although suppression of HIV
replication with first-line therapy is reported in up to 90% cases, virologic treatment failure may
still occur in patients treated with cART [
], limiting treatment options and
increasing the risk of death . A substantial prevalence of transmitted ARV resistance among newly
infected individuals is well documented [
]; up to 20% of untreated patients may
demonstrate resistance to ARV drugs in at least one class [
11, 12, 19–22
]. Since treatment failure is
frequently attributed to the presence or emergence of drug-resistant HIV-1 variants, [
ARVs with unique resistance profiles and high genetic barriers to resistance may improve
treatment outcome, by leveraging drugs with unique resistance profiles and higher genetic barriers
Based on in vitro data demonstrating slow evolution of PI resistance in HIV-1 isolates
exposed to TPV [
], this trial was conducted to observe if resistance could be minimized.
TPV, co-administered with ritonavir (TPV/r) to attain therapeutic concentrations [
achieved good virologic responses in a small treatment-naïve study [
] and in two large
tripleclass-experienced patient studies [
1, 2, 31
]. TPV/r was safe and well tolerated in the 14-day
naïve patient trial [
]. Forty-eight-week results from RESIST-1 and RESIST-2 show that TPV/
r 500/200 mg twice daily (BID), along with an optimized backbone regimen (OBR), had
superior efficacy in viral suppression and immunologic responses versus an investigator-selected,
ritonavir (RTV)-boosted comparator protease inhibitor (CPI/r) in more than 1400 highly
treatment-experienced patients [
The 1182.33 trial was conducted to evaluate the potential role of TPV/r in treatment-naïve
HIV-1-infected adults. In this 48-week, randomized, open-label trial, the efficacy and safety of
two dose combinations of TPV/r (500/200 mg or 500/100 mg BID) was compared with the
active control group, lopinavir plus ritonavir (LPV/r). Each treatment group also received a
standardized nucleoside/nucleotide backbone regimen. In vitro inhibition of wild-type HIV-1
2 / 17
is achieved with lower TPV concentrations than those seen with the 500/200 mg BID dose.
Therefore, the lower RTV dose was included for testing because it results in lower TPV
concentrations; these lower exposures with a 500/100 mg BID dose were projected to decrease adverse
effects of TPV and yet provide adequate inhibitory concentrations. In this report, we provide
the final trial data, and put the results into historical and clinical context.
Materials and Methods
HIV-1-infected men and women 18 years of age who have never previously been treated
with ART (up to 7 days of previous treatment was allowed), CD4+ cell count <500 cells/mm ,
viral load (VL) 5000 copies/mL of plasma HIV-1 RNA at screening, and acceptable
laboratory values were eligible. Those with Division of AIDS (DAIDS) grade 1 (2.5 × upper limit of
normal [ULN]) or higher transaminase levels; those who had used immunomodulatory drugs
within 30 days of study start or concomitant medications likely to significantly reduce plasma
levels of study drugs; and women who were pregnant/breastfeeding were excluded. Trial
participation was voluntary and written informed consent was obtained from all subjects. The
protocol, informed consent, and subject information form were reviewed and approved by the local
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) listed in S1 Appendix.
The CONSORT check list is presented as S2 Appendix. The trial was approved by each site’s
local Ethics Committee, before the start of the trial, and any amendments were approved
during the conduct of the trial. The authors confirm that all related Phase 2–4 trials for tipranavir
are registered. There are no longer any ongoing trials being conducted by the Sponsor.
This study was a multinational, multicenter trial conducted from March 2, 2004, to June 22,
2006, at 74 sites in Western and Eastern Europe, Canada, Australia, Latin America, and
Thailand. Patients were randomized to receive open-label TPV/r 500/100 mg BID, TPV/r 500/200
mg BID, or LPV/r 400/100 mg BID in combination with a backbone regimen of tenofovir
disoproxil fumarate (TDF) and lamivudine (3TC). Patients were randomized centrally at a ratio of
1:1:1 in blocks of six. Centers were restricted to no more than 40 patients. Randomization was
stratified by screening CD4 count ( 200 or >200 cells/mm3) but not by the center.
The primary efficacy endpoint was treatment response at week 48, defined as a confirmed
virologic response (two consecutive VL measurements 50 copies/mL) without prior virologic
failure, discontinuation of study drug, loss to follow-up, introduction of a new drug, or death.
Secondary efficacy endpoints included time to treatment failure (TTF), using VL <50 copies/
mL and VL <400 copies/mL as response criteria; treatment and virologic response at all visits,
using VL <50 copies/mL and VL <400 copies/mL as response criteria; change from baseline in
VL (log10 transformed) and CD4+ cell counts at each visit; patients with new Centers for
Disease Control (CDC) AIDS-defining illness or death; and time to new AIDS-defining illness or
death. Treatment failure is the complementary outcome to treatment success: the absence of
confirmed virologic response (two consecutive VL measurements, 50 copies/mL) without
prior virologic failure by week 48; discontinuation of study drug; loss to follow-up;
introduction of a new ARV drug (except for reason of toxicity); or death. An additional analysis of TTF
used 400 copies/mL as an alternative viral load threshold.
Safety endpoints were incidences of any adverse event (AE), any serious adverse events
(SAEs), or chemistry and hematology test abnormalities. Analysis included empirical
distribution of time to AEs and laboratory abnormalities of interest, including first SAE, grade 3/4
alanine aminotransferase (ALT) elevation, grade 3/4 aspartate aminotransferase (AST) elevation,
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occurrence of diarrhea and/or vomiting, grade 3/4 triglycerides abnormality, and grade 3/4
cholesterol abnormality. Provisions were made for treatment interruption to reduce
transaminase elevations in cases with grade 3 transaminase elevations.
Patient and investigator were blinded to treatment assignment until after all eligibility criteria
were met and the patient was randomized to his/her treatment assignment. Patients
randomized to the TPV/r200 group initially took TPV/r 500/100 mg BID for 2 weeks. The 2-week
lead-in regimen was used because the pre-steady state concentrations of TPV and RTV are
higher in patients without prior liver enzyme induction (e.g., treatment-naïve patients) than is
seen in patients with previous induction experience (e.g., treatment-experienced patients). This
strategy aimed at avoiding TPV concentrations above the target level during the early dosing
period in the 200 mg RTV group.
A backbone ARV regimen consisting of a nucleotide reverse transcriptase inhibitor (NtRTI,
TDF 300 mg) plus a nucleoside reverse transcriptase inhibitor (NRTI, 3TC 300 mg) once daily
was administered. A change from 3TC or TDF to another NRTI was allowed if toxicity or
intolerance was clearly attributed to backbone medication. Patients were considered for withdrawal
from the study and appropriate alternative therapy initiated if (i) VL had not dropped for at
least 0.5 log10 after the initial 12 weeks of treatment; and (ii) patients failed to achieve
VL < 100,000 copies/mL after 12 weeks of treatment, despite a 0.5 log10 copies/mL reduction
after 12 weeks; or (iii) had VL > 400 copies/mL confirmed at two consecutive visits >2 weeks
apart following a confirmed virologic response.
Plasma HIV-RNA concentrations, CD4+ cell counts, and safety laboratory evaluations were
performed for every visit while patients remained on study. Study visits were scheduled at 2, 4,
12, 24, 36, and 48 weeks and then every 12 weeks until study completion. HIV-RNA
concentrations were assayed and quantified using the Roche Amplicor1 HIV-1 Monitor Standard or
Ultrasensitive Assay, Version 1.5, by Covance Central Laboratory Services. Baseline HIV
genotypic resistance assessments were performed by VIRCO using their Virtual PhenotypeTM
assay. Phenotypes were determined using VIRCO’s Antivirogram assay.
The sample size was estimated using nQuery Advisor1 4.0 by using the simulation of the lower
confidence limit for difference in proportions for a one-sided 98.8% confidence interval (CI). A
sample size of 180 per group was needed to achieve an 80% power for response rate in all
groups of 70%. Primary efficacy analysis of available data was performed after all patients
completed week 48. Analyses were based on treatment assigned at randomization. Primary analysis
compared the treatment response of each TPV/r treatment group to that of the LPV/r group,
using a two-sided 97.5% CI for the difference in response rates, adjusted by baseline CD4 strata
(Bonferroni adjustment). Non-inferiority was concluded if the lower bound of the CI did not
exceed the pre-defined non-inferiority margin of 15%. Additional analyses of the primary and
secondary endpoints used descriptive statistics for all variables, logistic regression for treatment
and virologic response, analysis of variance (ANOVA) for change from baseline in VL and
CD4 count, and Cox proportional hazards and log-rank tests for time to event endpoints.
Analysis of binary endpoints followed the intention-to-treat (ITT) principle, where missing values
were replaced using the non-completers considered failures (NCF) approach. For continuous
endpoints, including VL and CD4+ cell counts, change from baseline missing values was
4 / 17
imputed for analysis using the last observation carried forward (LOCF) method. All analyses
were adjusted for CD4 strata.
Baseline patient characteristics
Demographics and patient baseline characteristics were similar between the three treatment
groups (Table 1). Median age was 35 years (range, 18–74); population was predominantly male
(76.5%) and white (73.3%). Median VL and CD4+ cell count for the ITT population were
similar across treatment groups (overall median of 5.03 log10 copies/mL and 207 cells/mm3,
respectively), as was rate of hepatitis B or C co-infection.
AIDS-defining illnesses, based on CDC classifications (Categories C1–C3), had occurred in
11.1% of patients prior to enrollment.
Baseline resistance characteristics and HIV-1 subtypes
Baseline genotyping and clade determination were performed in 535/562 randomized patients,
of whom 240/535 (44.9%) patients had no TPV score mutations (L10V, I13V, K20M/R/V,
Fig 1. Patient disposition up to study closure.
L33F, E35G, M36I, K43T, M46L, I47V, I54 A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and
]. Of those patients who had TPV score mutations present at baseline, 71.2% had one
or two, 24.7% had three, and 4.1% had four TPV score mutations. No patients had more than
four TPV score mutations at baseline. No patients had reverse transcriptase mutations
associated with the use of 3TC or TDF at baseline. Two patients had non-nucleoside reverse
transcriptase inhibitor (NNRTI) resistance mutations at baseline: K103N and V106I (a minor
etravirine mutation) [
]. The predominant HIV-1 viral subtype found in the patients in this
study was clade B (378/535 [70.7%]). There were 157 patients (29.3%) infected with non-B
subtype viruses, including subtype subtype F or BF, 8.6%; A/E mosaic (8.4%), subtype A (4.3%),
subtype C or C recombinant (4.3%) and subtype G (including AG or BG), 3.0%. A greater
proportion of non-B clade viruses at baseline had higher TPV mutation scores.
Fig 1 shows the patient disposition. In total, 562 subjects were eligible and randomized; of
these, four were not treated and three randomized to TPV/r100 but were treated with TPV/
r200. In total, 426/558 (76.3%) treated patients completed 48 weeks. Further, 132 (23.7%)
subjects prematurely discontinued therapy: 52/132 (39.4%) from the TPV/r100 group, 49/132
(37.1%) from the TPV/r200 group, and 21/132 (15.9%) from the LPV/r group. The primary
cause of patient discontinuation was AEs (9.1%) followed by loss to follow-up (5.0%),
withdrawn consent (3.0%), and virologic failure (1.8%). More patients in the TPV/r groups (9.8%
for the TPV/r100 and 14.8% for TPV/r200) than in the LPV/r group (2.7%) discontinued due
to AEs. Efficacy analyses included all 558 patients who were randomized and received at least
one dose of study medication.
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aLast viral load <50 copies/mL, without a subsequent confirming viral load <50 copies/mL
bViral load never was suppressed to <50 copies/mL
cConfirmed loss of virologic response to >50 copies/mL or loss of virologic response and missing confirmatory visit, by week 48
dIncludes premature discontinuation of the study protease inhibitor due to virologic failure and/or the addition of a drug to the backbone regimen (not
discontinued due to an adverse event attributable to the backbone drug)
eIncludes those events with fatal outcome with onset during the 48 week primary analysis treatment period
BID = twice daily, LPV/r = lopinavir/ritonavir, TPV/r = tipranavir/ritonavir, VL = viral load (plasma HIV-1 RNA).
Primary efficacy endpoint: Treatment response
Overall treatment response rates at week 48 were 68.4% (128/187) for the TPV/r100 group,
69.9% (130/186) for the TPV/r200 group, and 72.4% (134/185) for the LPV/r group. The CD4
strata-adjusted differences in response rates were −4.1 (97.5% CI: −14.5, 6.3) and −1.0 (97.5%
CI: −11.4, 9.4) for TPV/r100 and TPV/r200, respectively, versus LPV/r.
For the final, full dataset, both the TPV/r100 and TPV/r200 groups achieved non-inferiority
to the LPV/r group at 48 weeks (Table 2, Fig 2). Proportions with treatment response were
68.4%, 69.9% and 72.4% for the TPV/r100, TPV/r200 and LPV/r groups, respectively.
In the low CD4 stratum ( 200 CD4 cells/mm3) for VL <50 copies/mL, treatment response
rates at 48 weeks were 60.7% (51/84), 61.9% (52/84), and 62.0% (62/100) of patients in the
TPV/r100, TPV/r200, and LPV/r groups, respectively. Differences in low CD4 stratum
response rates were −1.2 (97.5% CI: −18.2, 15.8) and 0.1 (97.5% CI: −16.2, 16.4) for TPV/r100
and TPV/r200, respectively, versus LPV/r. The proportions of patients who achieved a
treatment response at 48 weeks were greater in the high CD4 stratum (>200 CD4 cells/mm3) than
the low CD4 stratum: 74.8% (77/103), 79.1% (68/86), and 81.2% (82/101) of patients in the
TPV/r100, TPV/r200, and LPV/r groups, respectively. The differences in high CD4 stratum
response rates were −6.4 (97.5% CI: −19.5, 6.6) and −2.1 (97.5% CI: −15.8, 11.6) for TPV/r100
and TPV/r200, respectively, versus LPV/r. The difference in response rates across strata can be
attributed to a higher rate of virologic failures in the low CD4 strata (22.8%) than in the high
strata (8.3%), with no notable differences among treatment groups.
Treatment response at week 48, analyzed using logistic regression and adjusted for CD4
stratum, indicated no significant difference in achieving a response across the treatment groups
(odds ratios [ORs] of 0.82 [CI: 0.52, 1.29; p = 0.3824] and 0.94 [CI: 0.60, 1.49; p = 0.8011] for
7 / 17
Fig 2. Treatment response up to week 48 (confirmed VL <50 copies/mL).
TPV/r100 and TPV/r200, respectively, versus LPV/r; overall p = 0.6648). CD4+ cell count at
baseline had a significant effect on treatment response in all treatment groups, with patients in
the low strata less likely to achieve a response than patients in the high strata (OR = 0.44 [CI:
0.30, 0.64]; p<0.0001). Participants entering the trial with baseline VL <100,000 copies/mL
demonstrated similar treatment responses (<50 copies/mL) at 48 weeks, regardless of the
treatment group (79.2%, 79.5%, and 81.2% for TPV/r100, TPV/r200, and LPV/r, respectively). The
response rate for patients with baseline VL 100,000 copies/mL was less for all three treatment
groups, with that for TPV/r100 being slightly lower than for other groups (56.7%, 62.7%, and
65.0% for TPV/r100, TPV/r200, and LPV/r, respectively). Following the primary endpoint and
the decision to discontinue the experimental therapy, there was a substantial decrease in the
number of patients who remained on assigned therapy (week 72, 71% [396/558]; week 84, 56%
[315/558]), rendering subsequent data difficult to interpret.
Treatment failure was predominately due to virologic failure (lack of confirmed VL <50
copies/mL) and discontinuation due to AEs (Table 2). Virologic failure rates were comparable
between treatment groups: 16.0% (30/187), 14.5% (27/186), and 15.1% (28/185) of patients in
the TPV/r100, TPV/r200, and LPV/r groups, respectively. Treatment failure due to AE-related
discontinuations was higher in the TPV/r groups than in the LPV/r group: 7.0% (13/187), 9.7%
(18/186), and 2.7% (5/185) of patients in the TPV/r100, TPV/r200, and LPV/r groups,
Secondary efficacy endpoints
TTF using a virologic threshold for failure of <50 copies/mL at 48 weeks was analyzed using a
Cox proportional hazards model, adjusting for CD4 stratum. Distributions of TTF were
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statistically different when comparing either TPV/r group to LPV/r, with Cox proportional
hazards p-values of 0.0017 (HR = 1.74 [95% CI: 1.39, 2.09]) and 0.0014 (HR = 1.81 [95% CI:
1.44, 2.18]) for TPV/r100 and TPV/r200, respectively, versus LPV. Similar results were
observed using <400 copies/mL as the threshold.
Virologic response rates, using VL <50 copies/mL (ITT-NCF analyses; Fig 2), VL <400
copies/mL, and 1 log10 drop in VL, were comparable across the groups. VL reduction from
baseline was rapid and sustained across all treatment groups (ITT-LOCF analyses). VL
reductions from baseline were sustained to week 48, with median changes from baseline at week 48
of −3.10 (interquartile range [IQR]: −2.70, −3.49), −3.15 (IQR: −2.67, −3.56), and −3.27 (IQR:
−2.77, −3.62) log10 copies/mL for TPV/r100, TPV/r200, and LPV/r, respectively. ANOVA
results for differences in VL at week 48 were not statistically significant between TPV/r100 and
LPV/r (0.136; 95% CI: −0.045, 0.317; p = 0.1412) and between TPV/r200 and LPV/r (0.117;
95% CI: −0.065, 0.298; p = 0.2088).
Immunological improvement from baseline was evident early in all treatment groups
(ITT-LOCF), with median increases of 55 (IQR: 15, 99), 52 (IQR: 20, 101), and 57 (IQR: 15,
99) cells/mm3 for TPV/r100, TPV/r200, and LPV/r, respectively, at week 2. Median increases
in CD4 cell count at week 48 were 172 (IQR: 104, 266), 175 (IQR: 95, 263), and 207 (IQR: 111,
275) cells/mm3 for the TPV/r100, TPV/r200, and LPV/r groups, respectively. ANOVA results
for differences in CD4 count at week 48 were not statistically significant between TPV/r100
and LPV/r (−19.42; 95% CI: −46.16, 7.322; p = 0.1543) and between TPV/r200 and LPV/r
(−12.47; 95% CI: −39.41, 14.46; p = 0.3634).
The number of patients who experienced AIDS-defining illness or death was similar among
all three groups (four in the LPV/r group, five in the TPV/r200 group, and eight in the TPV/
r100 group). The time to a treatment-emergent AIDS-defining illness or death was not
significantly different among treatment groups (Cox regression: p = 0.2176 comparing TPV/r100
versus LPV/r; p = 0.5024 comparing TPV/r200 versus LPV/r). Of these events, there were 2, 1,
and 5 deaths in the LPV/r, TPV/r200, and TPV/r100 groups, respectively. No deaths were
related to study medication, and no particular AIDS-defining illness predominated: PCP
(TPV/r100, 3 subjects), HSV (TPV/r200, 1; LPV/r, 1), tuberculosis (TPV/r200, 1; LPV/r, 1),
and 1 each with Kaposi’s sarcoma, leukoencephalopathy, immunoblastoma, lymphoma,
recurrent pneumonia, and wasting syndrome.
There was no evidence of reduced responses to TPV/r in patients infected with non-clade B
Resistance emergence evaluation
A subset of all 21 patients with virologic failure or rebound during study treatment underwent
on-treatment resistance testing to characterize the emergence of protease gene and reverse
transcriptase mutations. Evaluation of resistance patterns was determined using samples from
those patients with virologic failure by week 24 (nine patients from the TPV/r100 group, nine
from the TPV/r200 group, and three from the LPV/r group). Three TPV/r patients (one TPV/
r100: Q58E, two TPV/r200: I84V and I13V) developed a single mutation associated with TPV
during the study. Based on TPV half-maximal inhibitory concentration (IC50), the virus for all
three patients remained fully susceptible to TPV ( 3-fold change in IC50 compared to
wildtype control virus). There was no change in protease inhibitor (PI) phenotypic resistance
classification for any of these 21 patients.
Only the M184I/V mutation emerged as a reverse transcriptase mutation associated with
resistance to 3TC and TDF. There were 11/21 (52.4%) patients who displayed this mutation at
the time of treatment failure.
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aPercentages of patients with laboratory assays performed: TPV/r100 (n = 183); TPV/r200 (n = 187); LPV/r (n = 182)
bAfter continued treatment or following re-introduction after treatment interruption, transaminase elevations returned to grade 2 in more than 65% of
patients receiving either TPV/r200 or TPV/r100
cIncludes those events with fatal outcome with onset during the 48 week primary analysis treatment period and the post-48 week follow-up treatment
AE = adverse event, BID = twice daily, LPV/r = lopinavir/ritonavir, TPV/r = tipranavir/ritonavir.
Safety was assessed in all 558 patients who received at least one dose of study medication.
Proportions of patients who experienced at least one AE while on treatment were similar among
the three groups. SAEs and AEs leading to discontinuation tended to be more frequent among
TPV/r groups (Table 3).
The most frequently observed AEs across the three groups were diarrhea, nausea, headache,
nasopharyngitis, abdominal pain, and vomiting; however, gastrointestinal symptoms and
grade 3 or 4 plasma cholesterol were observed more frequently in the TVP/r groups (Table 3).
Overall, 72.8%, 75.7%, and 70.8% of TPV/r100, TPV/r200, and LPV/r patients, respectively,
experienced gastrointestinal (GI) AEs, few of which were severe in intensity: 2.2%, 3.7%, and
2.7% for TPV/r100, TPV/r200, and LPV/r, respectively (Table 4). Differences in
discontinuations due to AEs (19, 29, and 6 for TPV/r100, TPV/r200, and LPV/r, respectively) are largely
due to more TPV/r than LPV/r patients discontinuing due to GI AEs (7, 8, and 1 patients,
respectively) and ALT/AST elevations (5, 14, and 2 patients, respectively) (Table 4).
Sixty-eight (12.2%) patients experienced SAEs by week 48. The overall rate was similar for
the TPV/r100 group and TPV/r200 group (26 [14.1%] and 26 [13.8%] patients, respectively)
and tended to be lower for the LPV/r group (16 [8.6%] patients). However, the rate of
drugrelated SAEs was comparable among treatment groups (two reported for each group).
Patients in the TPV/r200 group had a higher incidence of grade 3/4 ALT elevations (21.9%)
compared to those in the TPV/r100 group (7.1%) and the LPV/r group (4.4%) (Table 3).
10 / 17
Kaplan-Meier estimates of time to first grade 3/4 ALT or AST elevation were higher in the
TPV/r200 group than the other two treatment groups: Grade 3/4 ALT at week 48,
approximately 15% for TPV/r200, 6% for TPV/r100, and 4% for LPV/r; for grade 3/4 AST at week 48,
approximately 8%, 3%, and 2.5%, respectively (log Rank p<0.0001 for ALT and p = 0.0061 for
AST compared to LPV/r). Elevated ALT or AST values at baseline and active hepatitis B or C
co-infection at baseline were associated with greater frequency of on-treatment grade 3/4 ALT
or AST levels for all three groups. ALT levels returned to grade 2 in all but one patient in the
TPV/r100 group, all but two patients in the TPV/r200 group, and all but two patients in the
LPV/r group. ALT levels remained stable at grade 3/4 or increased after TPV/r discontinuation
in one of these patients in each of the TPV/r200 and LPV/r groups. AST levels returned to
grade 2 in all patients in the TPV/r100 group, all but one patient in the TPV/r200 group, and
all but two patients in the LPV/r group. AST levels remained stable or increased after TPV/r
discontinuation in one of these patients in each of the TPV/r200 and LPV/r groups. Treatment
interruptions and discontinuations as a result of grade 3/4 ALT and AST elevations were most
common in the TPV/r200 group (22/41 [53.7%] and 12/19 [63.2%] patients with ALT and
AST elevations, respectively) and occurred at a higher frequency than in treatment-experienced
]. However, upon continued treatment or following re-introduction after treatment
interruption, transaminase elevations returned to grade 2 in more than 65% of patients
receiving either TPV/r200 or TPV/r100. There were no clinical hepatic events reported in any
of the trial patients, including those with ALT/AST elevations.
Incidences of grade 3 lipid abnormalities were similar across the groups and lower than in
previous TPV trials with treatment-experienced patients, with the exception of cholesterol in
11 / 17
the TPV/r200 group [
1, 2, 31
]. Grade 3 total cholesterol elevations were reported in 7.0%, 6.0%,
and 2.7% of patients in the TPV/r200, TPV/r100, and LPV/r groups, respectively. The
KaplanMeier estimate of time to first grade 3 cholesterol abnormality was higher in the TPV/r200
group compared to LPV/r (Log Rank p = 0.0300). There were no grade 4 elevations. Grade 3 or
4 triglyceride elevations were similar across treatment groups: 7.6% of patients in the TPV/
r100 group, 4.8% in the TPV/r200 group, and 5.5% in the LPV/r group. The Kaplan-Meier
estimates of time to first grade 3 or 4 triglyceride abnormalities showed no significant differences
between the TPV/r groups and the LPV/r group.
Other laboratory abnormalities were generally grade 1 or 2 and occurred with similar
frequencies among the three groups.
Based on the higher frequency of liver transaminase elevations in the TPV/r200 group, the
external Data Safety Monitoring Board recommended closure of this treatment group during
the post-48-week follow-up period of the trial. Since the primary objectives had been achieved
and continuing TPV/r100 was perceived as being less tolerable than standard of care for initial
cART, the trial was discontinued during the post-48-week follow-up, with 436 (76.3%) patients
(132 [71.7%], 140 [74.1%], and 164 [88.6%] patients in the TPV/r100, TPV/r200, and LPV/r
groups, respectively) in the trial at that time.
Trial 1182.33 explored the effectiveness and safety of TPV/r in treatment-naïve patients, using
the dose employed for HIV-1-infected patients harboring PI-resistant virus, along with a lower
investigational exposure to TPV, as a result of a lower dose of RTV (100 mg). Overall, the
results demonstrated that 500 mg TPV, administered with either 100 mg or 200 mg RTV,
achieved substantial VL reduction to undetectable levels and immunologic responses in
HIV1-infected treatment-naive patients. Treatment response (confirmed VL 50 copies/mL)
evaluated at 48 weeks showed that both the TPV/r100 and TPV/r200 were non-inferior to LPV/r,
based on a non-inferiority margin of 15%. Additionally, reduction in VL was rapid for all three
treatment groups, with between −1.5 and −2 log10 median decreases at 2 weeks. At 48 weeks,
similar VL reductions (greater than 3 log10 copies/mL) were observed for all three treatment
groups. Immunological recovery was evident in TPV and LPV groups, with sustained increases
in CD4+ cell count. These results support the potent antiviral effect of TPV. These final results
differ slightly from the preliminary results previously presented [
], because missing data on
one patient in the TPV/r100 group became available only after the Glasgow presentation. At
the time, it appeared that the TPV/r100 group exceeded the 15% boundary for non-inferiority
(treatment response for LPV/r: 72.4%; TPV/r100: 67.9%; [difference: −4.6% (−15.03, 5.8)]).
The response rates for TPV/r200 and LPV/r remain unchanged between the Glasgow meeting
and the final analyses ((treatment response for TPV/r200: 69.9%; [difference: −1.0% (−11.4,
It should be noted that since this trial was intended as the initial examination of TPV/r in
naïve patients, the sample size was modest and therefore the non-inferiority bound was set at
15%, since this was considered an exploratory Phase 2B trial.
Subset analysis using the baseline stratification of patients by CD4+ cell count and VL
showed similar results between treatment groups. As seen in studies of other treatment-naïve
patients, patients in the higher CD4+ strata were more likely to achieve treatment responses
HIV genotypes were mostly of clade B subtype, but the proportion of non-B subtypes with
three or four TPV score mutations was almost 40-fold greater than that of the B subtype at
baseline. Furthermore, the distribution of non-B subtypes was similar across treatment groups.
12 / 17
The Stanford University HIV Resistance Database shows that non-B subtypes tend to be more
TPV resistant [
]. Despite patients with non-B subtypes tending to have more TPV score
mutations at baseline, there was no evidence of meaningful response differences between clade
B and non-B subtypes.
The protease inhibitor polymorphisms detected at trial entry represent PI non-key mutations;
these polymorphisms differ from the key mutations, the presence of which results in high level PI
resistance. These polymorphisms almost certainly represent naturally occurring sequences and
are unlikely to imply any prior PI treatment in the study’s treatment naïve patients.
Testing of the post treatment isolates revealed no emergent phenotypic resistance upon
virologic rebound. Specifically, the phenotypic susceptibility classification did not change for any of
the 21 patients whose post-rebound isolates were tested. Reverse transcriptase mutation M184I/
V was identified in over half of the viruses from patients with virologic rebound, similar to that
reported previously in studies of PIs used with 3TC [
]. Absence of any emerging PI resistance
during treatment with TPV was expected due to the high genetic barrier to resistance, as has
been seen with other RTV-boosted PIs in HIV-1-infected treatment-naïve patients.
Most commonly reported AEs among all three treatment groups were GI events, mostly
moderate in intensity. Compared to the LPV/r group, both TPV/r groups had higher
discontinuations rates due to AEs, largely due to higher rates of discontinuation for GI AEs and
transaminase elevations in both TPV/r arms. The open-label design could have influenced
investigators’ decisions to discontinue therapy in TPV patients with GI events. However, a
majority of TPV/r200 patients with grade 3/4 transaminase increases could continue therapy
uninterrupted or after re-challenge, and levels returned to grade 2 in all instances. Fatalities
during the trial were uncommon among these treatment-naive patients; a total of nine (1.6%)
deaths were reported, of which eight were during treatment or within 30 days following drug
discontinuation. One occurred after 30 days of follow-up. Few episodes of treatment-emergent
AIDS-defining illnesses were reported. There were only six drug-related SAEs reported. The
results indicate that TPV meets the non-inferiority criteria used in this trial despite the
reported AE rates, based on the predefined non-inferiority margin of 15% (which is larger than
the current generally accepted margin of 10%–12%).
Finally, it should be noted that the results of this study suggest that TPV/r should not be
considered for use in treatment-naïve HIV patients. Although the trial demonstrated efficacy similar
to a standard of care at the time the trial was conducted, the safety and drug interaction profiles
 are not compatible with first-line therapy. Furthermore, the current standards of care have
evolved; neither the IAS-USA nor DHHS Guidelines now include LPV/r + TDF + 3TC as
firstline therapy [
]. Therefore, the first-line therapy standard to which TPV/r was compared is
no longer as relevant as it was in 2004–2006. Currently recommended first-line therapy is
generally recognized as having fewer drug-associated adverse events, a more manageable drug
interaction profile and more patient-friendly pill burden. For second-line or later therapy, it is critical
that new regimens contain at least 2 (preferably 3) active ARV drugs . Therefore, there may
be need for TPV/r-containing combination regimens in a small number of late-stage treatment
patients, who have developed PI resistance, and are unable to use other regimens.
In this trial, conducted in 2004–2006, both TPV/r100 and TPV/r200 regimens showed
sustained treatment responses in approximately 70% of patients, which were non-inferior to LPV/
r at 48 weeks. VL reductions and CD4+ cell count increases were similar among treatment
groups. However, these TPV/r regimens do not appear to be appropriate options among
currently available therapies for treatment-naïve patients. Current therapies have improved
13 / 17
adverse event and drug interaction profiles, as well as more patient-friendly pill burdens. The
authors suggest that TPV/r regimens should not be used for treatment-naïve patients.
S1 Appendix. List of local Independent Ethics Committees and Institutional Review boards
S2 Appendix. CONSORT check list
Writing, editorial support, and formatting assistance was provided by Dr. Annirudha Chillar,
MD, PhD of CACTUS communications, which was contracted and funded by Boehringer
Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the
manuscript for medical and scientific accuracy as well as intellectual property considerations. The
authors retained full control of the manuscript content.
Study team: Argentina: Pedro Cahn, Lidia Isabel Cassetti, Arnaldo Casiro, Hector
Laplumé, Lucia Esther Daciuk, Ana Leticia Gurini, Graciela Beatriz Torales. Australia: David
Cooper, Jenny Hoy, Cassy Workman, David Baker, Richard Moore, Norman Roth, John Quin,
Julian Gold. Bahamas: Perry Gomez. Brazil: Artur Timerman, Beatriz Grinsztejn, José
Ramalho Valdez Madruga, Marília Santini de Oliveira, Roberto Zajdenverg, Adauto Castelo
Filho, José Luiz de Andrade Neto. Canada: William Cameron, Brian Conway, Pierre Cote,
Kevin Gough, Richard Lalonde, Anita Rachlis, Stuart Rosser, Michael Silverman, Fiona Smaill,
Michel Boissonnault, Christos Tsoukas, Sharon Walmsley, Frederic Crouzat. Colombia: Carlos
Alvarez, Alvaro Arango, Ricardo Leal, Otto Sussmann. France: Laurent Cotte, Pr. Pierre-Marie
Girard, Jacques Reynes, Vincent Jeantils. Germany: Keikawus Aratéh, Frank Bergmann, Stefan
Esser, Gerd Fätkenheuer, Frank-Detlef Goebel, Mark Oette, Stefan Mauss, Albrecht Stoehr.
Mexico: Paulo Lopez, Eduardo Zapat, Mario Jáuregui. Poland: Andrzej Gładysz, Marek
Beniowski, Anna Boroń-Kaczmarska, Andrzej Horban. Romania: Dan Duiculescu, Adrian
Streinu Cercel. Russia: Elena Vinogradova, Vadim Pokrovsky. Spain: Jose Mª Gatell Artigas,
Bonaventura Clotet, Daniel Podzamczer, Mercedes Gurgui Ferrer, David Dalmau, Rafael
Rubio, Federico Pulido, Pompeyo Viciana, Manuel Márquez, José Luis Gómez–Sirvent. UK:
Margaret Johnson, Clifford Leen, Jonathan Ainsworth. Thailand: Kiat Ruxrungtham,
Sasisopin Kiertiburanakul, Chaiwat Ungsedhapand.
Conceived and designed the experiments: DAC KA JS RLC PR. Performed the experiments:
DAC DVC RZ KR KA FB JLAN RLC. Analyzed the data: DAC JS RLC PR. Contributed
reagents/materials/analysis tools: JS RLC PR. Wrote the paper: DAC DVC RZ KR KA FB
JLAN JS RLC PR.
14 / 17
Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined
data from two randomised open-label trials. Lancet. 2006; 368: 466–475. PMID: 16890833
15 / 17
16 / 17
1. Cahn P , Villacian J , Lazzarin A , Katlama C , Grinsztejn B , Arasteh K , et al. Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIVinfected patients: 24-week results of the RESIST-2 trial . Clin Infect Dis . 2006 ; 43 : 1347 - 1356 . PMID: 17051504
2. Hicks CB , Cahn P , Cooper DA , Walmsley SL , Katlama C , Clotet B , et al. Durable efficacy of tipranavirritonavir in combination with an optimised background regimen of antiretroviral drugs for treatmentexperienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic
3. Staszewski S , Morales-Ramirez J , Tashima KT , Skiest D , Stanford J , Stryker R , et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults . New England Journal of Medicine . 1999 ; 341 ( 25 ): 1865 - 1873 . PMID: 10601505
4. Günthard HF , Aberg JA , Eron JJ , Hoy JF , Telenti A , Benson CA , et al. Atiretroviral treatment of adult HIV infection 2014 -Recommendations of the International Antiviral society-USA Panel . Journal Amer Medical Assoc . 2014 ; 312 : 410 - 425 .
5. Clotet B , Feinberg J , van Lunzen J , Khuong-Josses MA , Antinori A , Dumitru I , et al. for ING114915 Study Team . Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study . Lancet . 2014 ; 383 : 2222 - 22231 . doi: 10 .1016/S0140- 6736 ( 14 ) 60084 - 2 PMID: 24698485
6. DeJesus E , Rockstroh JK , Henry K , Molina JM , Gathe J , Ramanathan S , et al., and GS- 236 -0103 Study Team . Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial . Lancet . 2012 ; 379 : 2429 - 2438 . doi: 10 .1016/S0140- 6736 ( 12 ) 60918 - 0 PMID: 22748590
7. Raffi F , Rachlis A , Stellbrink HJ , Hardy WD , Torti C , Orkin C , et al, and the SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study . Lancet . 2013 ; 381 : 735 - 743 . doi: 10 .1016/S0140- 6736 ( 12 ) 61853 - 4 PMID: 23306000
8. Molina JM , Lamarca A , Andrade-Villanueva J , Clotet B , Clumeck N , Liu YP , et al and the Study 145 Team. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study . The Lancet Infectious Diseases . 2012 ; 12 : 27 - 35 . doi: 10 .1016/S1473- 3099 ( 11 ) 70249 - 3 PMID: 22015077
9. Cahn P , Pozniak AL , Mingrone H , Shuldyakov A , Brites C , Andrade-Villanueva JF , et al and the extended SAILING Study Team . Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study . Lancet . 2013 ; 382 : 700 - 708 . [Erratum in Lancet 2014; 383 :30] doi: 10.1016/S0140- 6736 ( 13 ) 61221 - 0 PMID: 23830355
10. Cohen C , Wohl D , Arribas JR , Henry K , Van Lunzen J , Bloch M , et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults . AIDS . 2014 ; 28 : 989 -997 doi: 10. 1097/QAD.0000000000000169 PMID: 24508782
11. Rimsky L , Vingerhoets J , Van Eygen V , Eron J , Clotet B , Hoogstoel A , et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis . Journal of Acquired Immune Deficiency Syndromes: JAIDS . 2012 ; 59 : 39 - 46 . doi: 10 .1097/QAI.0b013e31823df4da PMID: 22067667
12. Vingerhoets J , Tambuyzer L , Azijn H , Hoogstoel A , Nijs S , Peeters M , et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies . AIDS . 2010 ; 24 : 503 - 514 . doi: 10 .1097/QAD.0b013e32833677ac PMID: 20051805
13. Ledergerber B , Egger M , Opravil M , Telenti A , Hirschel B , Battegay M , et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study . Swiss HIV Cohort Study. Lancet . 1999 ; 353 : 863 - 868 . PMID: 10093977
14. Cingolani A , Antinori A , Rizzo MG , Murri R , Ammassari A , Baldini F , 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 - 379 . PMID: 11834948
15. Fatkenheuer G , Theisen A , Rockstroh J , Grabow T , Wicke C , Becker K , et al. Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients . AIDS . 1997 ; 11 : F113 - F116 . PMID: 9386799
16. Ledergerber B , Lundgren JD , Walker AS , Sabin C , Justice A , Reiss P , et al. Predictors of trend in CD4- positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes . Lancet 2004 ; 364 : 51 - 62 . PMID: 15234856
17. Shet A , Berry L , Mohri H , Mehandru S , Chung C , Kim A , et al. Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-1: a decade of experience . J Acquir Immune Defic Syndr . 2006 ; 41 : 439 - 446 . PMID: 16652051
18. Patick AK , Duran M , Cao Y , et al. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir . Antimicrob Agents Chemother 1998 ; 42 : 2637 - 2644 . PMID: 9756769
19. Cane P , Chrystie I , Dunn D , Evans B , Geretti AM , Green H , et al. Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study . BMJ . 2005 ; 331 : 1368 . PMID: 16299012
20. Li JZ , Gallien S , Do TD , Martin JN , Deeks S , Kuritzkes DR , Hatano H. Prevalence and significance of HIV-1 drug resistance mutations among patients on antiretroviral therapy with detectable low-level viremia . Antimicrobial Agents & Chemotherapy . 2012 ; 56 : 5998 - 6000 .
21. Swenson LC , Min JE , Woods CK , Cai E , Li JZ , Montaner JS , Harrigan PR , Gonzalez-Serna A . HIV drug resistance detected during low-level viraemia is associated with subsequent virologic failure . AIDS 2014 ; 28 : 1125 - 1134 . doi: 10 .1097/QAD.0000000000000203 PMID: 24451160
22. Wittkop L , Gunthard HF , de Wolf F , Dunn D , Cozzi-Lepri A , de Luca A , et al. for the EuroCoord-CHAIN study group . Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study . The Lancet Infectious Diseases 2011 ; 11 : 363 - 371 . doi: 10 .1016/S1473- 3099 ( 11 ) 70032 - 9 PMID: 21354861
23. Larder BA , Hertogs K , Bloor S , van den Eynde CH , DeCian W , Wang Y , et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples . AIDS . 2000 ; 14 : 1943 - 1948 . PMID: 10997398
24. Boden D , Hurley A , Zhang L , Cao Y , Guo Y , Jones E , et al. HIV-1 drug resistance in newly infected individuals . JAMA . 1999 ; 282 : 1135 - 1141 . PMID: 10501116
25. Condra JH , Holder DJ , Schleif WA , Blahy OM , Danovich RM , Gabryelski LJ , et al. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor . J Virol . 1996 ; 70 : 8270 - 8276 . PMID: 8970946
26. 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 - 765 . PMID: 10950769
27. Havlir DV , Eastman S , Gamst A , Richman DD . Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients . J Virol 1996 ; 70 : 7894 - 7899 . PMID: 8892912
28. Doyon L , Tremblay S , Bourgon L , Wardrop E , Cordingley MG . Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir . Antiviral Res 2005 ; 68 : 27 - 35 . PMID: 16122817
29. 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 ; 55 : 371 - 382 .
30. McCallister S , Valdez H , Curry K , MacGregor T , Borin M , Freimuth W , 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 Acquir Immune Defic Syndr . 2004 ; 35 : 376 - 382 . PMID: 15097154
31. Gathe J , Cooper DA , Farthing C , Jayaweera D , Norris D , Pierone G Jr., et al. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial . Clin Infect Dis . 2006 ; 43 : 1337 - 1346 . PMID: 17051503
32. de Mendoza C , Morello J , Garcia-Gasco P , Rodriguez-Novoa S , Soriano V . Tipranavir: a new protease inhibitor for the treatment of antiretroviral-experienced HIV-infected patients . Expert Opin Pharmacother . 2007 ; 8 : 839 - 850 . PMID: 17425479
33. Johnson VA , Brun-Vézinet F , Clotet B , Gunthard HF , Kuritzkes DR , Pillay D , et al. Update of the drug resistance mutations in HIV-1: Spring 2008 . Top HIV Med . 2008 ; 16 : 62 - 68 . PMID: 18441382
34. Cooper D. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naive patients: results of BI 1182.33 . Paper presented at: 8th International Congress on Drug Therapy in HIV Infection , Glasgow, UK, 2006 .
35. King MS , Bernstein BM , Walmsley SL , Sherer R , Feinberg J , Sanne I , et al. Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients . J Infect Dis . 2004 ; 190 : 280 - 284 PMID: 15216462
36. Stanford HIVDB Team. Stanford University HIV Resistance Database. http://hivdb.stanford.edu/index. html. Accessed 08 November , 2012 .
37. Kempf DJ , King MS , Bernstein B , Cernohous P , Bauer E , Moseley J , et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine . J Infect Dis . 2004 ; 189 : 51 - 60 . PMID: 14702153 Aptivus Package Insert , Section 7 . Drug Interactions: http://bidocs.boehringer-ingelheim.com/ BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Aptivus/ Aptivus.pdf (revised February 2012 ).
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents . Department of Health and Human Services . Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 9 April 2015 .