Incidence of CXCR4 tropism and CCR5-tropic resistance in
treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1
and 2 trials
Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials. Resistance was assessed relative to number of active drugs in participants’ optimized background therapy, pharmacokinetic adherence markers, Baseline demographic data, HIV-1 RNA and CD4+ counts. For participants with R5 virus confirmed (post hoc) at Screening, Baseline genotypic weighted optimized background therapy susceptibility scores (gwOBTSS) were assigned where possible. Through Week 48, 219/392 (56%) participants with an assigned gwOBTSS achieved a virologic response. Of those remaining, 48/392 (12%) had CXCR4-using virus; 58/392 (15%) had R5 virus (maraviroc sensitive: n = 35/392, 9%; maraviroc resistant: n = 18/392, 5%; undeterminable: n = 5/392, 1%) and 67/392 (17%) had no failure tropism result. When optimized background therapy provided limited support to maraviroc (gwOBTSS <2), 143/286 (50%) responded to therapy, while 76/106 (72%) participants with gwOBTSS ≥2 responded (p < 0.001). Resistance rates were highest for participants with gwOBTSS <2, accounting for 45/48 (94%) of total CXCR4-using emergence and 18/18 (100%) of total CCR5-tropic resistance. R5 viruses from participants with gwOBTSS ≥2 (n = 10) were exclusively maraviroc sensitive; five of these participants had pharmacokinetic and/or pill-count markers of non-adherence. When co-administered with a fully active background regimen, maraviroc did not readily generate resistance in the clinical setting.Trial registry name:ClinicalTrials.gov (https://clinicaltrials.gov/), NCT00098722 and NCT00098306
Introduction<!>Study population<!>HIV tropism and maraviroc susceptibility determination<!>Susceptibility score determination<!>Pharmacokinetic measurements<!>Statistical analysis<!>Virologic outcomes and gwOBTSS participant populations<!><!>Virologic outcomes and gwOBTSS participant populations<!>Participant characteristics<!><!>HIV-1 tropism and R5 susceptibility at virologic failure<!><!>HIV-1 tropism and R5 susceptibility at virologic failure<!>Baseline resistance to maraviroc<!>Treatment outcomes for participants within the gwOBTSS virologic outcomes
population<!><!>Relationship between virologic outcome and activity of the background
regimen<!><!>Relationship between virologic outcome and activity of the background
regimen<!>Participants failing with maraviroc-susceptible virus<!>Comparison between participants failing with maraviroc-susceptible or
-resistant R5 virus<!><!>Comparison between participants failing with maraviroc-susceptible or
-resistant R5 virus<!>Discussion<!>Conclusions
<p>Maraviroc is a first-in-class CCR5 antagonist currently approved in the United States
for twice daily (BID) use in CCR5-tropic (R5) HIV-1-infected adults, adolescents and
children at least 2 years old who weigh at least 10 kg, (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208984_022128s017lbl.pdf)
and in Europe for antiretroviral treatment–experienced persons of the same age and
weight group (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000811/WC500022190.pdf).
In the Phase III MOTIVATE 1 and 2 studies, maraviroc (once daily [QD] or BID) plus
optimized background therapy (OBT) demonstrated significantly greater virologic and
immunologic efficacy and a similar safety profile compared with placebo plus OBT at
Week 48 in treatment-experienced participants with R5 virus (as identified using the
original Trofile® assay [Monogram Biosciences, South San Francisco, CA,
USA]).1,2 All participants
receiving maraviroc QD were offered maraviroc BID when the last patient had reached
Week 48 and the study was unblinded; overall responses were then durable with
maraviroc BID through to Week 96.3</p><p>In contrast to other antiretroviral drugs, maraviroc resistance does not manifest
itself in phenotypic drug susceptibility assays as a shift in half-maximal
inhibitory concentration (IC50) following serial in
vitro passage of virus with drug.4 This is thought to be a consequence of maraviroc's novel mode of action,
which involves binding to a host cell receptor rather than to a viral
component.5,6
Maraviroc binding to CCR5 provokes an allosteric conformational change, which
inhibits viral engagement with the coreceptor and prevents entry. Thus, rather than
mutating to prevent the drug from binding to its target, maraviroc resistance arises
when the virus mutates to make use of drug-bound CCR5. This is characterized
phenotypically in drug susceptibility assays by reduced maximum percent inhibition
(MPI) in which 100% inhibition of viral replication is not achieved even at
saturating drug concentrations.4 Such a mechanism has also been described for other CCR5 antagonists7,8 and was confirmed for maraviroc
in a pre-planned interim analysis of a subset of MOTIVATE participants.9</p><p>Detailed analysis of viruses obtained from participants enrolled in the MOTIVATE
studies demonstrated that virologic failure in participants receiving
maraviroc-containing regimens can occur either as a result of 'un-masking' of
pre-existing CXCR4-using virus (CXCR4- or dual-mixed tropic)10 or with R5 virus, which may or may not harbor phenotypic resistance to
maraviroc.4,11–13</p><p>As with other studies in treatment-experienced participants,14,15 pre-planned
subgroup analyses of the MOTIVATE studies demonstrated that more participants who
received a higher number of potentially active drugs in their OBT according to
Baseline susceptibility scores achieved virologic suppression.1 Subsequent post hoc analyses of the MOTIVATE virologic
population have shown that an alternative methodology, using a genotypic weighted
OBT susceptibility score (gwOBTSS), provides a more relevant measure of the
contribution of the OBT to the overall regimen antiviral activity than simply
counting active drugs. It also shows a significant correlation with treatment outcome.16</p><p>In the present study, we describe for the first time the maraviroc tropism and R5
virus resistance findings for the MOTIVATE studies at Week 48, the time of the
protocol-defined primary endpoint analysis, using the enhanced sensitivity Trofile
assay (ESTA)-derived population. In addition, the incidence of maraviroc resistance
in the MOTIVATE trials is reported and discussed in the context of activity of the
OBT.</p><!><p>MOTIVATE 1 and MOTIVATE 2 were parallel, randomized, double-blind,
placebo-controlled multinational Phase III studies.1,2 The two studies differed
only by geographic location, and all participants were infected with R5 HIV-1 at
Screening, as determined using a co-receptor tropism assay (original Trofile
assay), and had taken one or more agents from three antiretroviral classes for
six months or had documented genotypic or phenotypic resistance to drugs from at
least three classes of antiretroviral drug. Maraviroc (150 mg QD or BID) or
placebo was administered along with an optimized background of antiretroviral
drugs (i.e. OBT) based on treatment history and drug resistance testing.</p><p>The primary endpoint of the MOTIVATE 1 and 2 trials was the mean change in plasma
HIV-1 RNA concentration (log10 copies/mL) from Baseline.</p><p>In the current analysis, virologic failure was defined using time to loss of
virologic response criteria including failure to achieve plasma HIV-1 RNA <50
copies/mL (TLOVR50) by Week 48, discontinuation prior to Week 48 for lack of
efficacy or two consecutive plasma HIV-1 RNA measurements ≥50 copies/mL
occurring after a confirmed <50 copies/mL result. Participants who continued
therapy through Week 48 without meeting any of the above failure definitions
were considered responders. Failure tropism and maraviroc susceptibility were
assessed at discontinuation or Week 48, the primary endpoint visit.</p><p>The study protocols were approved by the institutional review board or
independent ethics committee at each study center (see Supplemental Table 1 for
a complete list). Written informed consent was obtained from all participants.
The studies were performed in accordance with International Conference on
Harmonisation Good Clinical Practice guidelines and applicable local regulatory
requirements and laws. The studies were registered with ClinicalTrials.gov
(identifiers: NCT00098722 and NCT00098306).</p><!><p>Tropism was determined from virus in plasma samples using the Trofile assay.
Possible results included CCR5-tropic (R5), CXCR4-tropic (X4) and dual- or
mixed-tropic (DM) virus. Dual-tropic and mixed-tropic viruses cannot be
distinguished in this assay. X4 and DM results may be classified together as
CXCR4-using virus. Enrolment into the MOTIVATE 1 and 2 trials required
participants to be infected with R5 HIV-1, as determined using the original
Trofile assay. However, after conclusion of the trials, a more sensitive method
for detection of CXCR4-using virus became available (ESTA)17 and a retrospective reanalysis of Screening tropism was performed to
identify participants with detectable, pre-existing CXCR4-using virus. These
participants would not have been enrolled if ESTA had been available at the time
of the trials.</p><p>Maraviroc susceptibility was determined by Monogram Biosciences using the
PhenoSense® HIV-1 Entry assay and was described in terms of both IC50
fold change (FC) and MPI. Resistance was defined as virus with MPI <95%,
based on previous findings with in vitro generated
maraviroc-resistant viruses4,18 and studies of
participants failing early in the MOTIVATE trials.9</p><!><p>Sequencing of the reverse transcriptase and protease at Screening was performed
by Monogram Biosciences. Enfuvirtide was genotypically assessed at the BC Centre
for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. Genotypic
susceptibility scores and overall susceptibility scores were provided by
Monogram Biosciences, who used their proprietary algorithms.</p><p>The gwOBTSS was determined as described previously.16 In brief, the results were interpreted using the French National Agency
for AIDS Research (ANRS) algorithm (ANRS-AC 11: Resistance group, July 2008,
version n°17) and, together with treatment history, were used to determine
gwOBTSS. Drugs in continuous use pre-screening through Week 48 or earlier
discontinuation were not counted, as drugs already present in a prolonged,
stable, failing regimen pretreatment do not contribute to post-Baseline
responses. In addition, based on data showing that active nucleosides contribute
only approximately 50% of the virologic activity of drugs from other classes in
treatment-experienced participants,19 active nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) were
assigned a score of 0.5. Protease inhibitors (PIs) with an 'intermediate'
resistance genotype scored 0.5 and other active agents scored 1.0.</p><p>The ANRS algorithm has since been updated (ANRS-AC 11: Resistance group,
September 2017, version n°27). The effects of this change on the gwOBTSS
analysis was determined for participants included in the analysis of the
relationship between the gwOBTSS and maraviroc susceptibility, with no changes
in gwOBTSS among the 53 participants.</p><!><p>Sparsely sampled random pharmacokinetic (PK) measurements (1–2 per visit) were
performed during visits for the first 24 weeks of therapy. Samples with
maraviroc concentrations below the limit of quantification (0.5 ng/mL; BLQ) were
considered to display a marker of poor adherence.20</p><!><p>Differences between maraviroc log10 IC50 FC of R5 viruses
at Baseline and failure time points were tested using a paired
t-test. To compare maraviroc MPIs, the Wilcoxon matched
pairs test was employed. Differences in treatment outcomes and failure tropism
between gwOBTSS groups and treatment arms were analyzed using a Chi-squared
test. Odds ratios and Wald 95% confidence intervals (CIs) were calculated by
dichotomizing the variables. While medians were used for age (<43 vs.
≥43 years) and time since diagnosis (<13 vs. ≥13 years), for CD4 and HIV-1
RNA, 100 cells/µL and 100,000 copies/mL, respectively, were used as the
cut-offs. A continuity correction of 0.5 was applied for calculating the odds
ratios.</p><!><p>Of 841 participants enrolled in the MOTIVATE 1 and 2 trials with R5 virus at
Screening as assessed using ESTA, 663 received at least one dose of maraviroc
(Figure 1).</p><!><p>Participant accountability. BID, twice daily; ESTA, enhanced sensitivity
Trofile assay; gwOBTSS, genotypic weighted optimized background therapy
susceptibility score; OBT, optimized background therapy; QD, once daily.
1. Includes adverse events n = 31, default
n = 37, death n = 6 and other
n = 15. 2. Exclusions were based on the same
criteria as described previously.16 Briefly, these include Baseline visit >7 days before start of
randomized therapy (n = 3), OBT changes while
on-treatment or drug use changes between the Screening and OBT windows
(n = 129), OBT drugs that had an interruption of
treatment that could have resulted in an incorrect gwOBTSS score
(n = 22) and unavailable resistance test result for
an OBT drug (n = 34). More than one event could have
occurred with any given participant. The OBT window was a period of
seven days either side of the 'Day 1' Baseline study visit for the OBT
to be initiated.</p><!><p>To focus on the mechanisms associated with virologic failure, 89 participants who
discontinued for non-virologic reasons were excluded from the analysis to give a
total of 574 maraviroc recipients with a known virologic outcome at Week 48 (the
Virologic Outcomes Population). To study participants who had a consistent OBT
through Week 48, only participants to whom a gwOBTSS could be assigned were
included in the current analysis (392/574, 68%, the gwOBTSS Virologic Outcomes
Population). Failure to assign a gwOBTSS score was due to potential confounding
factors, the most common of which was a change in OBT during blinded therapy
(n = 129) (Figure 1). The total Virologic Outcomes placebo group consisted of
178 participants with R5 virus at Screening, established using the ESTA.</p><!><p>Baseline characteristics of the 574 maraviroc-treated participants with virologic
outcomes and the 392 participants with a valid gwOBTSS were similar to those of
the entire cohort of 1049 enrolled participants2 and were balanced between treatment groups (Table 1).</p><!><p>Baseline demographic characteristics of participants studied in this
sub-analysis compared with the full participant population for the
MOTIVATE trials and the gwOBTSS Virologic Outcomes Population.</p><p>Virologic Outcomes Population</p><p>n = 574</p><p>Full participant population</p><p>n = 1049</p><p>Population</p><p>n = 392</p><p>Exclusions</p><p>n = 182</p><p>gwOBTSS: Genotypic weighted optimized background therapy
susceptibility score.</p><!><p>A treatment response (HIV-1 RNA <50 copies/mL at Week 48) was observed at Week
48 in 311 of the 574 (54%) participants in the Virologic Outcomes Population,
and a further 81 (14%) participants had insufficient plasma HIV-1 RNA (<500
copies/mL) for tropism testing. CXCR4-using virus was detected at failure or
Week 48 in 75 (13%) participants; 87 (15%) participants failed with R5 virus and
20 (3%) participants had a non-reportable tropism result. Of the 87 participants
failing with R5 virus, virus from 53 (61%) showed maraviroc sensitivity, 26
(30%) had selected resistance to maraviroc and 8 (9%) did not have both Baseline
and failure maraviroc susceptibility data available.</p><p>When the two maraviroc treatment arms (QD and BID) were compared, there was no
significant difference in the distribution of outcomes or viral tropism at
failure between the BID and QD arms (p = 0.13, Chi-square
test), and the proportion of evaluable R5 viruses with maraviroc resistance was
comparable between treatment arms at failure (p = 0.82,
Chi-square test).</p><p>In the group of 79 participants experiencing failure with R5 virus and with
successful paired Baseline and failure maraviroc susceptibility determinations,
there was no difference between IC50 FC at Baseline and failure
(geometric mean IC50 FC Baseline: 0.75, 95% CI: 0.67–0.84; failure:
0.78, 95% CI: 0.69–0.87, p = 0.5, paired
t-test; Figure
2(a)) . However, a significant difference was observed between
maraviroc MPI at Baseline and failure (MPI mean ± standard deviation: Baseline:
99.3 ± 1.9, range 88–100%; failure: 91.3 ±15.8, range 13–100%,
p < 0.0001, Wilcoxon matched pairs test; Figure 2(b)).</p><!><p>Sensitivity of R5 viruses to maraviroc at Baseline and at the last on
treatment determination at TLOVR50 failure. Sensitivity assessed by (a)
maraviroc IC50 compared with reference strain (JRCSF)
(excludes two participants whose virus was not inhibited to 50% at the
highest concentration of maraviroc used in the assay), and (b) maraviroc
MPI. Differences between log10 IC50 FCs tested
using paired t-test. Differences between MPIs tested
using the Wilcoxon matched pairs test. FC: fold change; IC50:
half-maximal inhibitory concentration; MPI: maximum percent inhibition;
TLOVR50: time to loss of virologic response criteria including failure
to achieve plasma HIV-1 RNA <50 copies/mL.</p><!><p>In a sensitivity analysis, a snapshot, virology-first approach was used to
identify per-protocol participants who did not have <50 copies/mL at Week 48
and who did not discontinue treatment because of adverse events or death. These
were assessed for tropism and maraviroc susceptibility at failure. Of 243
virologic failures, 151 had valid tropism determinations at failure; of these,
67 were CXCR4-using and 84 had R5 virus. Seventy of those with R5 virus had
maraviroc susceptibility data, and of these, 24 showed resistance. These values
were comparable to those for the analysis based on TLOVR50 failure.</p><p>In the total Virologic Outcomes placebo group, 122 of 178 participants (69%)
showed virologic failure; 113 (63%) had >500 copies/mL plasma HIV-1 RNA and
were eligible for tropism assessment: 7 (6.2%) had CXCR4-using tropism, 8 (7.1%)
failed tropism testing, and 98 (87%) had R5 virus at failure. Twenty-one of
these 98 participants had maraviroc susceptibility data, one of whom showed
resistance with an MPI of 41%.</p><!><p>Phenotypic resistance to maraviroc was identified at Baseline in three
participants in the Virologic Outcomes Population who later experienced failure
with R5 virus. Two of these participants had Baseline MPIs of 92% and 88%, which
further reduced during therapy to 80% and 56%, respectively. Virus from the
remaining participant had a Baseline MPI of 93% but maraviroc-sensitive virus
(MPI >95%) was found at failure.</p><!><p>A significant association between virologic response and the Baseline gwOBTSS and
CD4 counts was previously demonstrated in a post hoc analysis
of MOTIVATE 1 and 2.16 To examine the relationship between failure with maraviroc-resistant R5
virus and Baseline factors, a retrospective analysis was performed using the
ESTA-derived gwOBTSS Virologic Outcomes Population. Proportions of participants
with each outcome were consistent with the Virologic Outcomes Population
described above. Just over half of participants (219/392, 56%) responded to
treatment through Week 48; 58 of 392 (15%) participants failed with R5 virus and
48 of 392 (13%) participants failed with X4 or DM virus (Figure 3). In the original gwOBTSS
Virologic Outcomes Population sub-group (i.e. that included participants with
CXCR4-using virus detected at Screening using ESTA) (n = 493),
a slightly lower proportion of participants responded to treatment (260/493,
53%), with a corresponding increase in the proportion of participants
experiencing failure with X4 or DM virus (n = 91/493, 18%)
(Supplemental Figure 1).</p><!><p>TLOVR50 outcome and viral tropism at failure. This analysis was performed
with the ESTA-derived gwOBTSS Virologic Outcomes Population
(n = 392). R5: failure with R5-tropic virus; X4/DM:
failure with CXCR4-using virus; <500 copies/mL: failure with HIV-1
plasma RNA below cut-off for tropism determination; NR/NP: tropism
result not available. ESTA: Enhanced Sensitivity Trofile Assay; gwOBTSS:
genotypic weighted OBT susceptibility score; TLOVR50: time to loss of
virologic response criteria including failure to achieve plasma HIV-1
RNA <50 copies/mL.</p><!><p>The relationship between gwOBTSS and TLOVR50 outcome at Week 48 in the 392
participants in the ESTA-derived gwOBTSS Virologic Outcomes Population was
assessed. Significantly more participants with gwOBTSS ≥2 responded to the
maraviroc-based regimens (76/106, 72%) than in those with less background
antiretroviral activity (gwOBTSS <2: 143/286, 50%;
p < 0.001, Chi-square test). Further breakdown of gwOBTSS
groups confirmed the increase in response with gwOBTSS (gwOBTSS: <1: 53/132,
40%; 1–1.5: 90/154, 58%; ≥2: 76/106, 72%, p < 0.0001,
Chi-square test) (Figure
4(a)). There was no significant difference in the distribution of
outcomes between the QD and BID treatment arms.</p><!><p>Outcomes, (a) failure tropism and (b) R5 maraviroc susceptibility in the
ESTA-derived gwOBTSS Virologic Outcomes Population by gwOBTSS. R5:
failure with R5-tropic virus; X4/DM: failure with CXCR4-using virus;
<500 copies/mL: failure with HIV-1 plasma RNA below cut-off for
tropism determination; NR/NP: tropism result not available. ESTA:
Enhanced Sensitivity Trofile Assay; gwOBTSS: genotypic weighted OBT
susceptibility score.</p><!><p>CXCR4-using failure accounted for 25/132 (19%), 20/154 (13%) and 3/106 (3%) of
the population in the <1, 1 to 1.5 and ≥2 gwOBTSS groups, respectively, and
R5 failure accounted for 31/132 (23%), 16/154 (10%) and 11/106 (10%) of the
population across these gwOBTSS groups, respectively. The proportion of R5
viruses with phenotypic resistance to maraviroc at failure changed significantly
with gwOBTSS (p = 0.01, Chi-square test). Indeed, 45/48
failures with CXCR4-using virus and 18/18 failures with R5-viral resistance on
failure had regimens with gwOBTSS <2 (Figure 4). There was no significant
difference in the proportion of failure with maraviroc-resistant virus between
the QD and BID treatment arms.</p><p>A similar pattern was observed in the original Trofile-derived gwOBTSS Virologic
Outcomes Population with the proportion of participants responding to therapy
increasing with gwOBTSS and failure with R5-tropic resistance being most
prevalent in participants with a gwOBTSS of 0 to 0.5 and not observed at gwOBTSS
≥2 (Supplemental Figure 2).</p><!><p>Additional analyses were performed to assess why failure occurred in participants
with virus that was fully sensitive to maraviroc (n = 35),
including 10 with gwOBTSS ≥2. One possible explanation was poor adherence to
therapy. The absence of detectable plasma maraviroc, pill count and the
variability of the modeled PK parameters over the period of sparse sampling
(through Week 24) was assessed for evidence of poor adherence to maraviroc. For
this analysis, 6 of the 35 participants were excluded due to the absence of PK
data at failure (five of seven with rebound failed after Week 24; one other did
not have a plasma maraviroc concentration available). Of the remaining 29
participants with maraviroc-sensitive R5 virus at failure, 15 were found with
evidence of poor adherence including five of eight (62.5%) who received a
regimen with optimal antiretroviral activity (gwOBTSS ≥2), five of nine (55.6%)
with gwOBTSS of 1 to 1.5, and 5 of 12 (41.7%) received a weak or inactive
regimen (gwOBTSS <1).</p><!><p>To further explore the reasons for failure with R5 virus with resistance, an
analysis of potential parameters associated with R5 failure having maraviroc
resistance was performed (Figure 5).</p><!><p>Odds ratio determinations for demographic, pharmacokinetic, and virologic
characteristics of participants with virologic failure with R5 virus.
(a) Odds ratios and 95% CIs for prediction of resistance among R5
failures. (b) Change in MPI between Screening and failure in
participants treated with gwOBTSS ≤0.5. (c) Change in MPI between
Screening and failure among participants with gwOBTSS >0.5. Odds
ratios were calculated based on high and low values based on > or ≤
median values for continuous variables or on stratification criteria
(CD4 cell count: 100 cells/mm3; HIV-1 RNA: 100,000 copies/mL;
age: 43 years old; time since diagnosis: 13 years; GSS and OSS: 2;
gwOBTSS: 0.5). A continuity correction of 0.5 was applied. CI:
confidence interval; GSS: genotypic susceptibility score; gwOBTSS:
genotypic weighted OBT susceptibility score; MPI: maximum percent
inhibition; OSS: overall susceptibility score.</p><!><p>None of the demographic or PK parameters shown in Figure 5 produced any odds ratios
indicating a significant relationship between these and the outcome of virologic
susceptibility to maraviroc. The only significant finding was that of the
gwOBTSS (OR, 4.78 [95% CI, 1.37–16.67] for resistance with gwOBTSS <1.0). In
addition, resistance was observed only in instances where there was always
detectable maraviroc in plasma when sparse sampling was performed (17/17). Poor
adherence, as assessed by the absence of detectable maraviroc in plasma on
sparse sampling, was found in 7/34 participants failing with
maraviroc-susceptible R5 virus.</p><!><p>Previously we have examined in detail an interim data set based on a Week 24 data cut
for the first 267 participants enrolled in the MOTIVATE trials.9 In the current analysis, only viruses from participants with R5 viral
infections at Screening as determined using ESTA were included for the whole
clinical data set through Week 48, the time of the primary endpoint analysis. The
earlier analysis allowed for a more detailed clonal analysis in a smaller number of
participants to establish principles of tropism pre-existence
(n = 20) and to further examine mutations that might be associated
with resistance to maraviroc in R5 virus (n = 4).9 The current analysis differs in that it describes the incidence of maraviroc
resistance in the larger Week 48 data set (48 failures with CXCR4 virus and 58 with
R5 virus, 18 of which showed maraviroc resistance in the maraviroc-treated groups)
and examines potential clinical correlates of maraviroc resistance.</p><p>Another study examined the correlates of virologic failure in relation to the
background regimen activity and other clinical parameters using the data from the
population identified with the original screening Trofile assay.16 The current post hoc analysis expands on that analysis to
describe the incidence of R5-tropic maraviroc resistance in the participants
included in the ESTA-derived MOTIVATE populations who experienced virologic failure
and further explores potential correlates of such resistance. Overall, 56% of
participants with a virologic outcome for whom a valid gwOBTSS could be assigned
achieved a TLOVR50 response through Week 48. Twelve percent of participants had
CXCR4-using virus detected at the time of failure; 15% of the population failed with
R5 virus and 31% of these had maraviroc-resistant R5 virus detected, the majority of
whom had gwOBTSS 0 to 0.5. Findings were similar when failure was identified using
either TLOVR50 or snapshot criteria.</p><p>It has been suggested that the proportion of participants failing with CXCR4-using
virus in the MOTIVATE studies was higher than that observed in trials of another
CCR5 antagonist, vicriviroc, in treatment-experienced participants.21 The current MOTIVATE re-analysis demonstrates that retrospective exclusion of
participants with CXCR4-using virus detected using ESTA at Screening does indeed
decrease the proportion of CXCR4-using viruses observed at treatment failure with
maraviroc. The majority of the remaining participants who went on to have detectable
CXCR4-using virus at failure had weakened support from their OBTs. Such participants
represented approximately twice the proportion of the MOTIVATE study population
compared with that in the vicriviroc Phase III VICTOR study, in which an overall
greater proportion of participants had fully active antiviral support from the OBT
(OBT fully active drugs, unweighted: ≤2: MOTIVATE: 72%–75%; VICTOR: 36%).1,22</p><p>Consistent with maraviroc's mode of action, and as previously reported for in
vitro generated maraviroc-resistant viruses and in other clinical
studies with other CCR5 antagonists,8,21,23 resistance to CCR5 antagonists
was characterized by a significant reduction in MPI rather than an increase in
IC50 FC. Binding of maraviroc to the host protein, CCR5, rather than
to a viral target, results in the virus becoming resistant via mutations that
promote entry through gp120 recognition of the drug-bound receptor. As there is no
dependency on the virus for drug binding, the concentration required to achieve full
occupancy of cell-surface CCR5, when susceptible virus would show 100% inhibition,
remains unaltered. However, even with full occupancy, resistant virus can achieve
entry, albeit with reduced efficiency, and so the degree of inhibition is less than
100%.</p><p>Antiviral activity of the background drugs in the participant's regimen was reported
previously as an important determinant of treatment outcome in this highly
treatment-experienced population.16 While maraviroc provided benefit when added to a regimen with any gwOBTSS,
the correlation between gwOBTSS and response rate suggests that optimal benefit is
obtained from its addition to regimens while options for optimization with fully
active drugs remain.</p><p>Consistent with this, most participants who failed therapy with maraviroc-resistant
R5 virus had gwOBTSS <1, and so the main selective pressure exerted by their
treatment regimen was from maraviroc with little or no support from other drugs.
These findings are similar to those from trials with vicriviroc,21,24 in which four
of five treatment-experienced participants with vicriviroc-resistant R5 virus had an
overall susceptibility score of 0, and with raltegravir,15 where the majority of integrase mutations were identified in virus from
participants failing treatment with a genotypic or phenotypic susceptibility score
to their OBT of 0. Under conditions of functional monotherapy, any
maraviroc-resistant virus emerging would be expected to become the dominant species
as it replicates in the presence of maraviroc-selective pressure, unchecked by other
components of the treatment regimen. However, the finding that a third of
participants treated with functional maraviroc monotherapy successfully achieved and
maintained viral suppression demonstrates sufficient antiretroviral activity in
these individuals to reduce viral replication to levels where resistance to
maraviroc is not readily generated, even in the absence of an active OBT.</p><p>In contrast, maraviroc-resistant R5 viruses were not detected in any participants
with gwOBTSS ≥2. In this group, where effective treatment was achieved with regimens
including at least three active antiretroviral drugs, several drugs with varying
modes of action maintained viral suppression sufficiently to prevent resistance
arising and 72% of participants achieved sustained viral suppression. Plasma
maraviroc concentrations were available for eight participants in this group who
also failed with maraviroc-sensitive R5 virus. Periods of incomplete adherence to
maraviroc therapy could be identified in all but one participant. During such
periods, a lack of drug pressure provides an opportunity for the replication of
drug-sensitive virus.</p><p>The study is limited by the diversity of the treatments employed, which was required
because of the advanced disease stage and degree of treatment experience in the
study population. Because the more recently developed integrase strand transfer
inhibitors as well as darunavir were not approved for use at the time of the study,
there were limitations on the treatment options available to participants. This will
have contributed to the low weighted scoring of antiretroviral activity in the
regimens, especially whenever continued use of a drug in enrollees occurred after
prolonged use on a failing regimen. Difficulties in maintaining advanced-stage
participants on one background regimen also contributed to the number of confounding
data sets. Despite this, the results reinforce the importance of an adequately
active background regimen and patient adherence in the treatment of HIV.</p><!><p>In summary, failure of maraviroc-based therapy with maraviroc-resistant R5 virus was
uncommon with the incidence related inversely to the number of active drugs in the
participants' background regimens. Maraviroc as functional monotherapy or with weak
antiviral support from the OBT accounted for approximately 50% of CXCR4-using
failure and 80% of R5 phenotypic resistance observed in the MOTIVATE gwOBTSS
Virologic Outcomes Population. In the presence of a fully active background therapy
(gwOBTSS ≥2), reduced proportions of CXCR4-using viruses were observed and R5
failure was exclusively maraviroc sensitive and related to markers of non-adherence
to therapy.</p>