Ensayo clinico Truvada kaletra vs Truvada Maraviroc en Profilaxis postexposición para Infeccion por VIH

1. A randomized clinical trial comparing ritonavir-boosted lopinavir versus
maraviroc each with tenofovir plus emtricitabine for post-exposure
prophylaxis for HIV infection
Lorna Leal1,2, Agathe Leo´n1,2, Berta Torres1, Alexy Inciarte1, Constanza Lucero1, Josep Mallolas1, Montserrat Laguno1,
Marı´a Martı´nez-Rebollar1, Ana Gonza´lez-Cordo´n1, Christian Manzardo1, Jhon Rojas1, Judit Pich1, Joan A. Arnaiz1,
Josep M. Gatell1,2 and Felipe Garcı´a1,2* on behalf of the MARAVIPEP Study Group†
1
Infectious Diseases Unit, Hospital Clı´nic of Barcelona, University of Barcelona, Barcelona, Spain; 2
Institut d’Investigacions Biome`diques
August Pi I Sunyer (IDIBAPS), Barcelona, Spain
*Corresponding author. Infectious Diseases Unit, Hospital Clı´nic, Villarroel, 170, 08036 Barcelona, Spain. Tel: +34932275586; Fax: +34934514438;
E-mail: fgarcia@clinic.ub.es
†Members are listed in the Acknowledgements section.
Received 29 September 2015; returned 17 November 2015; revised 15 January 2016; accepted 4 February 2016
Objectives: The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28,
comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the
backbone.
Methods: We conducted a prospective, open, randomized clinical trial. Individuals attending the emergency
room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized
to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted
lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1,
10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were
adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov:
NCT01533272.
Results: One-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and
120 to maraviroc (n¼237). PEP non-completion at day 28 was 38% (n¼89), with significant differences
between arms [ritonavir-boosted lopinavir 44% (n¼51) versus maraviroc 32% (n¼38), P¼0.05]. We
performed a modified ITT analysis including only those patients who attended on day 1 (n¼182). PEP non-
completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus
13%, P¼0.004). The proportion of patients with low adherence was similar between arms (52% versus
47%, P¼0.56). Adverse events were reported by 111 patients and were significantly more common in the ritona-
vir-boosted lopinavir arm (72% versus 51%, P¼0.003). No seroconversions were observed during the study.
Conclusions: PEP non-completion and adverse events were both significantly higher in patients allocated to ritona-
vir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this
setting.
Introduction
Considerable emphasis is now placed on prevention strategies
involving ART.1
Post-exposure prophylaxis (PEP) is a 28 day course
of ART recommended for persons who have had a potential
exposure to HIV. Results from animal studies2
indicate that ade-
quate compliance is necessary for PEP to be effective; however,
compliance is often limited by frequent drop-outs and the toxicity
of antiretroviral drugs such as PIs.3 – 5
The search for better toler-
ated regimens is a priority.
Maraviroc has been shown to be well-tolerated and may be
considered as a candidate for PEP.6
In animal models maraviroc
has demonstrated preventive effectiveness as a microbicide,7
while recent studies in HIV-negative women and men have found
that the drug reaches higher concentrations in the cervico-vaginal
tract and rectal mucosa than in plasma.8,9
Here, we examined whether tenofovir disoproxil/emtricitabine
plus maraviroc would achieve better completion rates, adherence
and tolerability than would tenofovir disoproxil/emtricitabine plus
ritonavir-boosted lopinavir.
# The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother
doi:10.1093/jac/dkw048
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2. Methods
We performed an open, randomized clinical trial at a tertiary-care hospital
in Barcelona. Participants were individuals who attended the emergency
room (ER) between April 2012 and July 2014 due to a potential sexual
exposure to HIV. Risk assessment and PEPrecommendation were performed
according to Spanish guidelines.10
Individuals who were ≥18 years old,
resident in Barcelona and who agreed to participate and signed informed
consent were randomized to receive tenofovir disoproxil/emtricitabine
(245/200 mg) once daily plus either ritonavir-boosted lopinavir
(400/100 mg) twice daily or maraviroc (300 mg) twice daily. A full 28 day
prescription was given and initiated immediately (day 0). A computer-
generated list of numbers was used to randomize participants. Prophylactic
measures for other sexually transmitted infections (STIs) were adminis-
tered.10
Owing to our hospital’s protocols we were not able to perform HIV
testing in the ER, and therefore HIV-negative status could not be confirmed
before starting PEP. After randomization, five follow-up visits were scheduled
for days 1, 10, 28, 90 and 180. The primaryendpoint was PEP non-completion
at day 28. PEP non-completion was considered when the patient was lost to
follow-up before day 28, when treatment was discontinued or switched for
any reason, or if the patient died. Secondary endpoints were: being lost to
follow-up at days 1, 28, 90 and 180; low adherence to PEP; number
of adverse events; and rate of seroconversions. The study was approved by
the hospital’s research ethics committee (approval number: HCP/2011/106)
and was registered in ClinicalTrials.gov: NCT01533272.
The day 1 visit was scheduled with an infectious diseases specialist
within 72 h of starting PEP. Demographics, risk behaviour, history of STIs
and previous PEP were recorded. As part of the risk assessment, we also
gathered information about the sexual partner: hepatitis C virus, hepatitis
B virus and HIV serostatus, ART and level of detection of viral load. This
information was conferred by our patients; we had no access to any
other personal information of partners or that enabled us to identify
them. Laboratory monitoring and sexual risk exposure counselling were
performed and repeated at days 28, 90 and 180. Treatment adherence
was reinforced on days 1, 10 and 28. Adherence was measured on day
28 with the Simplified Medication Adherence Questionnaire.11
The degree
of adherence can be calculated based on a patient’s responses and for the
present study we classified ≤94% as low adherence, a cut-off that has
also been adopted by other authors.12,13
Adverse events were assessed
and graded at every scheduled visit, following WHO recommendations.14
Statistical analysis
The sample size was calculated with a 1-b statistical power of 90% and a
protection level versus the bilateral a Type I error of 5%, assuming a treat-
ment discontinuation of 51% in the ritonavir-boosted lopinavir arm and
30% in the maraviroc arm, and a 30% of unevaluable patients.
An ITTanalysis was performed considering PEP non-completion at day
28. Since we had no information about treatment initiation in individuals
who did not attend any of the scheduled visits, we hypothesized that rea-
sons for non-attendance could be independent of the regimen prescribed.
Hence, we also performed a modified ITT analysis considering patients
who attended at least on day 1. Theindividualswho discontinued PEP because
they were found to be HIV positive on day 1 or because the sexual partners
subsequently were found to be HIV negative were excluded from this analysis.
Continuous variables were compared by means of the Student’s t-test or the
Mann–Whitney U-test. Categorical variables were compared using either
the x2
test or Fisher’s exact test. Backward logistic regression (Wald) was
performed to assess the independent factors associated with PEP non-
completion at day 28. Statistical analysis was conducted using SPSSw
20.
Results
A total of 237 individuals were randomized to receive tenofovir
disoproxil/emtricitabine plus either ritonavir-boosted lopinavir
(n¼117) or maraviroc (n¼120). The study flow chart is shown
in Figure 1. Participants were mostly MSM. The level of risk was
appreciable (defined as any sexual exposure excluding those of
low risk) in 83% of individuals (13% high and 70% moderate).
Characteristics of exposed individuals are shown in Table S1 (avail-
able as Supplementary data at JAC Online). HIV infection was
detected in three randomized patients at the day 1 visit and
they were referred to an HIV clinic to continue follow-up.
PEP non-completion
Only 187 individuals (79%) of those who were randomized
attended the first scheduled visit, there being no differences in
loss to follow-up between arms (P¼0.87) (Figure 1). PEP non-
completion at day 28 was 38% (n¼89), with significant dif-
ferences between arms (ritonavir-boosted lopinavir 44% versus
maraviroc 32%, P¼0.05). We performed a modified ITT analysis
including only those patients who attended the day 1 visit and
excluding individuals who discontinued PEP because they tested
HIV positive on day 1 (n¼3) or because the sexual partner subse-
quently tested HIV negative (n¼2) (n¼182). Characteristics of
this subgroup are shown in Table S1. PEP non-completion in this
subgroup was higher in the ritonavir-boosted lopinavir arm
(27% versus 13%, P¼0.004), as was the proportion of patients
lost to follow-up (21% versus 11%, P¼0.02). Only a few patients
discontinued PEP or switched treatment due to adverse events
(Figure 1). The Simplified Medication Adherence Questionnaire
was administered on day 28 and showed that the proportion
of patients with low adherence to PEP was similar between
arms (ritonavir-boosted lopinavir 52% versus maraviroc 47%,
P¼0.56). There were no seroconversions during this study.
Factors associated with PEP non-completion
The factors associated with PEP non-completion were analysed
(Table 1). The logistic regression model showed that being in the
ritonavir-boosted lopinavir arm (P¼0.015), non-Caucasian ethni-
city (P,0.0001), a low risk of exposure (P,0.0001) and previous
PEP (P¼0.005) were independent factors associated with PEP
non-completion.
Adverse events
There were 353 adverse events in 111 individuals (Table S2). No
grade III or IV adverse events related to medication were
reported. All adverse events resolved. Regarding laboratory abnor-
malities at day 28, no significant differences between groups were
observed and all were resolved at day 90.
Discussion
In this study, we found that rates of PEP non-completion and
adverse events were significantly higher in patients allocated
to ritonavir-boosted lopinavir, as compared with maraviroc.
Additionally, non-Caucasian individuals with a low risk of exposure
and those who had had previous PEP had a significant and inde-
pendent higher risk of PEP non-completion.
The present study was conducted concurrently with another
one15
of similar characteristics and using the same methods,
which compared ritonavir-boosted lopinavir with raltegravir,
both with tenofovir disoproxil/emtricitabine as the backbone,
Leal et al.
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3. and we found that rates of loss to follow-up, poor adherence and
adverse events were significantly higher in patients allocated to
the ritonavir-boosted lopinavir arm.
In line with previous reports,16,17
21% of the individuals who
were initially randomized in our study did not attend any of the
follow-up visits; furthermore, drop-out rates increased over
time, such that only one-third of participants completed all
6 months of follow-up. This is an important limitation to our
study, since adverse events, laboratory changes or seroconver-
sions could not be assessed in this group and might represent a
Table 1. Factors associated with PEP non-completion at day 28 due to any cause or to adverse events
Characteristic
PEP discontinuations due to any cause in the entire
cohort (n¼237), OR (95% CI)
PEP discontinuations due to any cause in patients who
attended the day 1 visit (n¼182), OR (95% CI)
Type of analysisa
univariate multivariate univariate multivariate
Randomization arm:
ritonavir-boosted lopinavir
1.3 (1.0–1.7), P50.05 2.6 (1.2–5.4), P50.015 2.9 (1.3–3.6), P50.006 2.9 (1.2–6.6), P50.015
Race: non-Caucasian 2.1 (1.6–2.8), P<0.0001 5.6 (2.5–12.3), P<0.0001 2.2 (1.0–4.5), P50.04 3.5 (1.5–8.4), P50.005
Risk assessment: low 1.2 (1.1–1.4), P50.009 5.3 (2.1–12.9), P<0.0001 4.8 (2.1–11.2), P<0.0001 5.5 (2.1–13.7), P<0.0001
Previous PEP: yes 1.4 (1.1–1.7), P<0.0001 3.3 (1.5–7.7), P50.005 1.6 (0.6–4.2), P¼0.32
Presence of adverse events
due to PEPb
: no
0.3 (0.4–2.7), P¼0.46
Bold formatting represents significant P values.
a
Individuals attending the day 1 visit with an HIV-positive test at baseline or with an HIV-negative partner were excluded from analysis.
b
Not measured in patients not attending the day 1 visit.
Randomized n=237
On study ART n=82 (68%)
Switch ART n=1 (1%)
Discontinuation AEs n=1 (1%)
n=24 (21%)
n=20 (17%)
n=26 (22%)
n=10 (8%)
n=22 (18%)
n=12 (10%)
n=51 (44%)
n=22 (19%)
n=24 (21%)
n=94 (78%)
Maraviroc arm (n=120)Day 0
Assessed for eligibility
(n=661)
*Excluded (424)
Not meeting inclusion criteria (220)
Declined to participate (56)
Other reasons (148)
Day 1
Day 28
Day 90
Day 180
n=62 (52%)
n=27 (23%) n=50 (42%)
On study ART n=66 (56%)
Switch ART n=2 (2%)
Discontinuation AEs n=5 (4%)
n=93 (79%)
Ritonavir-boosted lopinavir
arm (n=117)
Figure 1. Study flow chart. Day 0: randomization in the ER and treatment immediately initiated. Black boxes represent individuals on follow-up
according to arm. Grey boxes represent individuals lost to follow-up according to arm. Percentages in each box were calculated according to
individuals randomized to each arm. Day 1: patients that attended first follow-up visit scheduled with an infectious disease specialist within 72 h
after treatment initiation and individuals lost to follow-up to day 28. Day 28: patients who attended day 28 and individuals lost to follow-up to day
90 (on study ART patients who continued with the same ART received at day 0, those patients who switched to other medication but continued
receiving medication and attended day 28, and those patients who discontinued medication due to side effects and attended day 28). Day 90:
patients who attended day 90 and individuals lost to follow-up to day 180 visit. Day 180: patients who attended day 180 and completed the study.
AEs, adverse events.
Post-exposure prophylaxis for HIV
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4. threat for efficacy and generate safety issues, as well as limiting
any conclusions that can be drawn from the results. We consider
that in addition to tolerability of the PEP regimen, the possible rea-
sons for drop-out include pill-burden, difficulties accessing the
health system and a non-anonymous environment, a reduced
perception of risk, easier access to non-clinical community orga-
nizations and rapid HIV/STI tests.
Adherence was also compromised to a similar extent as in pre-
vious reports.18,19
In the present study both antiretrovirals were
prescribed twice daily and missing doses were frequently
reported, which suggests that a single tablet three-drug regimen
could improve outcomes.20
Contrary to what we expected, the presence of adverse events
related to PEP was not associated with non-completion. A pos-
sible explanation for this could be that although adverse events
were frequently described by participants, most were mild, well
tolerated and easily resolved.
Other limitations to our study are that we only included sex-
ual exposures and only 8% of our studied population were
women. Different outcomes may therefore have been observed
with parenteral risk and with a sample that was more balanced
by gender.
In summary, we observed an improvement in PEP completion
and toxicity with a maraviroc-containing regimen, suggesting that
maraviroc is a well-tolerated candidate for prophylactic use.
Acknowledgements
This study was presented at the Twenty-second Conference on
Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2015
(Abstract 959).
We would like to thank other members of the MARAVIPEP Study Group
for their invaluable collaboration.
Members of the MARAVIPEP Study Group
Lorna Leal, Agathe Leo´n, Berta Torres, Alexy Inciarte, Constanza Lucero,
Jose´ L. Blanco, Esteban Martı´nez, Josep Mallolas, Josep M. Miro´,
Monserrat Laguno, Jhon Rojas, Marı´a Martı´nez-Rebollar, Ana Gonza´lez-
Cordo´n, Carlos Cervera, Ana del Rı´o, Christian Manzardo, Juan Manuel
Perica´s, Gemma Sanclemente, Nazaret Cobos, Cristina de la Calle, Laura
Morata, Alejandro Soriano, Gerard Espinosa, Judit Pich, Joan A. Arnaiz,
Jose M. Gatell and Felipe Garcı´a.
Funding
This work was supported by Red Tema´tica Cooperativa de Grupos de
Investigacio´n en Sida (RIS) del Fondo de Investigacio´n Sanitaria (FIS)
grant SAF2012-39075 and by Pfizerw
.
Transparency declarations
Research funding, consultancy fees, lecture sponsorships or served on
advisory boards: F. G., Abbott, BMS, Gilead Sciences, ViiV, Janssen and
MSD; and J. M. G., Abbott, Boehringer Ingelheim, BMS, Gilead Sciences,
GSK, MSD, Pfizer, Theratechnologies and Tibotec. All other authors: none
to declare.
ViiV Healthcare reviewed a preliminary version of this manuscript for
factual accuracy. The authors are solely responsible for final content and
interpretation.
Author contributions
L. L., A. L., J. M. G. and F. G. contributed to the design of the clinical
study. L. L., A. L., B. T., A. I., C. L., J. M., J. R., M. L., M. M.-R., A. G.-C., C. M.,
J. P., J. A. A. and F. G. contributed to the implementation of the clinical
protocol. L. L., A. L., A. I., J. P., J. A. A. and F. G. contributed to the data
analysis and interpretation of the results. L. L., A. L., J. M. G. and
F. G. contributed to the writing of the manuscript. All authors approved
the final manuscript.
Supplementary data
Tables S1 and S2 are available as Supplementary data at JAC Online (http://
jac.oxfordjournals.org/)
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