Clinical Trial Truvada + Kaletra o Raltegravir en Profilaxis Preexposicion VIH

1. A randomized clinical trial comparing ritonavir-boosted lopinavir
versus raltegravir 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 RALPEP 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 28 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 two regimens.
Methods: A prospective, open, randomized clinical trial was conducted at a tertiary hospital in Barcelona, Spain.
Individuals attending the emergency room because of potential sexual exposure to HIV were randomized to
tenofovir disoproxil/emtricitabine (245/200 mg) plus either ritonavir-boosted lopinavir (400/100 mg) or raltegra-
vir (400 mg). 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: NCT01576731.
Results: One-hundred-and-twenty-one individuals were randomized to receive ritonavir-boosted lopinavir and
122 to raltegravir (n¼243). PEP non-completion at day 28 was 43% with no significant difference between
arms. We performed a modified ITT analysis including only those patients who attended on day 1 (n¼191).
PEP non-completion in this subgroup was higher in the ritonavir-boosted lopinavir arm than in the raltegravir
arm (34.6% versus 20.4%, P¼0.04), as was the number of patients lost to follow-up at day 28 (32.6% versus
21.6%, P¼0.08) and the proportion of patients with low adherence (49.2% versus 30.8%, P¼0.03). Adverse
events were significantly more common in the ritonavir-boosted lopinavir arm (73.4% versus 60.2%,
P¼0.007). There was an HIV seroconversion at day 90 in the raltegravir arm in a patient who had multiple
potential sexual risk exposures before and after receiving PEP.
Conclusions: Although we found no differences between arms regarding PEP non-completion, poor adherence
and adverse events were significantly higher in patients allocated to tenofovir disoproxil/emtricitabine plus
ritonavir-boosted lopinavir. These data support the use of raltegravir as the preferred third drug in current PEP
recommendations.
Introduction
The most effective method for preventing HIV infection is primary
prevention. However, accidental exposures to HIV do sometimes
occur. In these situations, the use of antiretroviral drugs has
been proposed as a secondary prevention measure. This is
known as post-exposure prophylaxis (PEP). Despite the lack of evi-
dence regarding its efficacy, PEP prescription has been accepted
based on animal studies,1
occupational PEP2
and on prophylaxis
of maternal–fetal transmission.3
According to animal studies, PEP must be correctly maintained
for 4 weeks to be effective.1
However, correct compliance with PEP
could be limited by the toxicity of ART. Side effects of PEP vary con-
siderably depending on the patient, leading to irregular treatment
protocols and drop-outs.4 –7
For nearly 10 years the most widely recommended PEP regi-
men involved the use of two nucleoside/nucleotide reverse tran-
scriptase inhibitors as backbone (zidovudine/lamivudine or
tenofovir/emtricitabine) with a third antiretroviral, preferably a
PI such as ritonavir-boosted lopinavir or atazanavir.8 – 10
Drop-
outs have frequently been described with these regimens, as
have toxicities, often attributed to the PIs.5
A study conducted
in healthcare workers showed that antiretroviral toxicity in a PEP
treatment protocol was up to six times greater than with the
# 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/dkw049
1 of 7
Journal of Antimicrobial Chemotherapy Advance Access published March 18, 2016
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

2. same treatment in HIV-positive individuals, leading to up to eight
times more drop-outs in the former group.11
The WHO PEP guidelines have recently been reviewed by an
expert panel that examined topics such as the optimal number
of drugs to prescribe, the preferred drugs to use and adherence
strategies.12
Because of this review, new recommendations are
available. The WHO now recommends tenofovir plus lamivudine
or emtricitabine, together with a third antiretroviral, preferably
ritonavir-boosted lopinavir or ritonavir-boosted atazanavir in
resource-limited settings, and as alternatives, ritonavir-boosted
darunavir, raltegravir or efavirenz, where available.13
Latest reviews of PEP guidelines in some well-resourced set-
tings consider raltegravir-containing regimens to be a good alter-
native for PEP given this drug’s tolerability and small number of
interactions. In fact, it has been selected as the preferred HIV
PEP regimen in the latest update of the United States Public
Health Service Guidelines and Spanish PEP Guidelines.14 –16
However, although raltegravir is now recommended as a
standard of care in some countries, there are, to our knowledge,
no clinical trials comparing its tolerability and treatment comple-
tion with that of ritonavir-boosted lopinavir, which remains a
standard of care in European and WHO guidelines.9,13
The Hospital Clinic in Barcelona has an HIV Unit with a PEP
programme, and since 2003 it has become the reference centre
for individuals with HIV-risk exposures (occupational, non-
occupational, sexual assault) in the city. In 2014, we prescribed
more than 600 PEP treatments. Given the lack of clinical trials
comparing the most recently recommended PEP regimens, our
team decided to perform an open, randomized clinical trial to
assess whether tenofovir disoproxil/emtricitabine plus raltegravir
would achieve better completion rates, adherence and tolerabil-
ity, and produce fewer adverse events, than would tenofovir dis-
oproxil/emtricitabine plus ritonavir-boosted lopinavir.
Methods
We performed an open, randomized clinical trial. Participants were indivi-
duals who attended the emergency room (ER) of our hospital between
November 2012 and June 2014 due to potential sexual exposure to HIV.
Risk assessment and PEP recommendation were performed according to
Spanish guidelines.17
We included individuals that were ≥18 years old and
resident in Barcelona who agreed to participate and who signed informed
consent. They were then randomized to receive tenofovir disoproxil/
emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopi-
navir (400/100 mg) twice daily or raltegravir (400 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.
Occupational exposures and individuals who had had contact with an HIV-
infected patient with known resistances to ART were excluded.
Prophylactic measures for other sexually transmitted infections (STIs)
were administered following Spanish recommendations.17
Counselling
and risk assessments were performed. 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 ran-
domization in the ER, five follow-up visits were scheduled for days 1, 10,
28, 90 and 180. The primary endpoint 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, total
number of adverse events and rate of seroconversions. The study was
approved by the hospital’s research ethics committee (approval reference
number: HCP/2011/181) and by the competent Spanish authorities. This
study was registered in ClinicalTrials.gov: NCT01576731.
The day 1 visit was scheduled with an infectious disease 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 (HCV),
hepatitis B virus (HBV) 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 anything that
enabled us to identify them. Laboratory monitoring (including HIV and
other STIs) 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. The day 10 visit was intended as an intermediate
assessment of adverse events and laboratory results from day 1; no
blood test was performed during this visit. Adherence was measured at
day 28 with the Simplified Medication Adherence Questionnaire (SMAQ),
a tool designed to identify non-adherent patients receiving ART. This six-
item instrument, which is reliable and easy to apply, has been validated
in the Spanish population and performs similarly to other adherence
assessment tools such as electronic measurement.18
The degree of adher-
ence 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.19,20
Adverse events were assessed and graded
at each scheduled visit, following WHO recommendations for monitoring
the toxicity of antiretrovirals.21
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 treat-
ment discontinuation of 51% in the ritonavir-boosted lopinavir arm and
30% in the raltegravir arm, and 30% of unevaluable patients.
An ITTanalysis was performed considering PEP non-completion at day
28. In addition, since we had no information about patients actually start-
ing treatment until they attended the day 1 visit, we hypothesized that
reasons for not attending could be independent of the type of medication
(i.e. pill burden, reconsideration of risk, costs, etc.). Consequently, we also
performed modified ITT analysis considering all patients who attended at
least the day 1 visit; the aim here being to assess better the effect of medi-
cation on PEP non-completion. The individuals who 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 between groups with the
Student’s t-test or the non-parametric Mann–Whitney U-test. Categorical
variables were compared between groups using the x2
test or Fisher’s
exact test. A backward logistic regression (Wald) was used to assess the
independent factors associated with PEP non-completion at day 28.
Statistical analysis was performed using SPSSw
20.
Results
Characteristics of exposed individuals and source
partners
From November 2012 until June 2014, 243 individuals attending
the ER for potential sexual exposure to HIV and who met criteria
for receiving PEP were randomized to receive 28 days of treatment
with tenofovir disoproxil/emtricitabine plus either ritonavir-
boosted lopinavir (n¼121) or raltegravir (n¼122). Figure 1
shows the study flow chart. Median age was 33 years, 90%
were males and 81% were MSM. Level of risk was appreciable
(defined as any sexual exposure excluding those of low risk) in
86% of individuals (9% high and 77% moderate).17
Fifty-eight
Leal et al.
2 of 7
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

3. (24%) individuals had received PEP previously and 13 (5%) had
done so more than once. Previous STIs were frequent [24%
(syphilis 44% and gonorrhoea 26%)]. HIV serostatus of the sexual
partner was known in 77 exposures (32%): 74 (30%) were HIV
positive and 3 were HIV negative (1 in the ritonavir-boosted lopi-
navir arm and 2 in the raltegravir arm); in addition, 1 partner
(0.4%) was co-infected with HCV and another (0.4%) with HBV.
Of 74 source partners who were known to be HIV infected,
39 (53%) were on ART (33 with undetectable viral load) and
14 (19%) were off ART; in 21 partners (28%) this information was
not available. HIV infection was detected in four randomized
patients in the serology performed on day 1 (two in the ritonavir-
boosted lopinavir arm and two in the raltegravirarm). These patients
were referred to an HIV clinic to continue follow-up. A few patients
were infected by HBV (n¼4), HCV (n¼4) or syphilis (n¼4) at day 1.
Characteristics of the exposed individuals are shown in Table 1.
PEP non-completion
Only 198 individuals of those who were initially randomized
(n¼243, 81.5%) attended the first scheduled visit (day 1), there
being no difference between the arms (21 individuals lost to
follow-up in the ritonavir-boosted lopinavir arm and 24 in the
raltegravir arm, P¼0.62) (Figure 1). PEP non-completion at day
28 was 43% (n¼105) with no significant differences between
arms [ritonavir-boosted lopinavir 48% (n¼58) versus raltegravir
39% (n¼47), P¼0.17]. We performed a modified ITT analysis
including only those patients who attended the day 1 visit
(n¼191) and excluding individuals who discontinued PEP because
they were found to be HIV positive on day 1 (n¼4) or because the
sexual partner subsequently were found to be HIV negative
(n¼3). Characteristics of this subgroup are shown in Table 1.
PEP non-completion in this subgroup of patients was significantly
higher in the ritonavir-boosted lopinavir arm (34 of 98 patients,
34.6%) than in the raltegravir arm (19 of 93 patients, 20.4%,
P¼0.04). The proportion of patients lost to follow-up at day 28
was also higher in the ritonavir-boosted lopinavir arm (32.6%
versus 21.6% in the raltegravir arm, P¼0.08). Only a few patients
discontinued PEP due to adverse events (n¼4: three in the
ritonavir-boosted lopinavir arm and one in the raltegravir arm).
Switching PEP was also rare (n¼2: one in the ritonavir-boosted
lopinavir arm and one in the raltegravir arm) (Figure 1). Most
patients who discontinued or switched PEP did not attend the
day 28 visit (9 of 15 patients).
The SMAQ was administered on day 28 and showed that the
proportion of patients with low adherence to PEP was higher in
Randomized n=243
On study ART n=74 (61%)
Switch ART n=1 (1%)
Discontinuation AEs n=1 (1%)
n=21 (17%)
n=33 (27%)
n=24 (20%)
n=21 (17%)
n=21 (17%)
n=27 (22%)
n=38 (31%)
n=30 (25%)
n=12 (10%)
n=97 (80%)
Raltegravir arm (n=121)Day 0
Assessed for eligibility
(n=583)
*Excluded (n=340)
Not meeting inclusion criteria (n=160)
Declined to participate (n=119)
Other reasons (n=61)
Day 1
Day 28
Day 90
Day 180
n=55 (45%)
n=26 (21%) n=28 (23%)
On study ART n=64 (52%)
Switch ART n=1 (1%)
Discontinuation AEs n=3 (2%)
n=101 (83%)
Ritonavir-boosted lopinavir
arm (n=122)
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
3 of 7
JAC
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

4. the ritonavir-boosted lopinavir arm (49.2% versus 30.8% in the
raltegravir arm, P¼0.03).
There was an HIV seroconversion at day 90 in the raltegravir
arm in a patient who had multiple potential sexual risk exposures
before and after receiving PEP.
Factors associated with PEP non-completion
The factors associated with PEP non-completion were investi-
gated (Table 2). In the multivariate (logistic regression) model,
age below the median (P¼0.02), female gender (P¼0.02),
non-Caucasian ethnicity (P¼0.002) and previous PEP (P,0.0001)
were independent factors associated with higher rates of PEP
non-completion.
Other factors such as the interval between exposure and PEP,
risk assessment, previous STIs or HIV testing, HIV infection of
source partner and the presence of adverse events were not asso-
ciated with PEP non-completion.
Adverse events
Adverse events could only be analysed in patients who attended
at least on day 1 (Table 3). There was a mean of 2.5 adverse
events/patient in the ritonavir-boosted lopinavir arm and a
mean of 2.1 adverse events/patient in the raltegravir arm. A
total of 268 (89%) adverse events were grade I, while the remain-
ing 33 were grade II, there being no differences between arms
(P¼0.07). No grade III or IV adverse events related to medication
were reported. The number of adverse events related to the PEP
regimen (defined as a definite, probable or possible relationship)
was 271 (90%) [167 (92.7%) in the ritonavir-boosted lopinavir
arm and 103 (85.1%) in the raltegravir arm, P¼0.03]. All adverse
Table 1. Characteristics of exposed individuals from the entire cohort (n¼243) and individuals coming at least to the day 1 visit (n¼191)
Characteristic
Entire cohort Coming at least to the day 1 visita
ritonavir-boosted
lopinavir raltegravir P
ritonavir-boosted
lopinavir raltegravir P
Number 243 121 122 191 98 93
Age (years), median (IQR) 33 (29–39) 32 (28–38) 34 (30–39) 0.07 34 (29–40) 32 (26–39) 34 (30–41) 0.03
Male, n (%) 218 (90) 108 (89) 110 (90) 0.77 175 (92) 89 (91) 86 (93) 0.44
Caucasian, n (%) 173 (71) 90 (74) 83 (68) 0.27 125 (65) 68 (69) 57 (61) 0.15
MSM, n (%) 196 (81) 96 (79) 100 (82) 0.52 156 (82) 77 (79) 79 (85) 0.17
Interval between exposure and
initiation of PEP (h), median (IQR)
14 (5–24) 15 (6–30) 12 (4–24) 0.13 15 (6–26) 16 (8–33) 12 (4–24) 0.04
Appreciable risk of infectionb
, n (%) 209 (86) 105 (87) 104 (85) 0.73 165 (86) 85 (87) 80 (86) 0.53
Previous PEP, n (%) 58 (24) 28 (23) 31 (25) 0.68 33 (17) 16 (16) 17 (18) 0.39
Previous STIs, n (%) 58 (24) 26 (21) 32 (26) 0.39 55 (29) 30 (31) 25 (27) 0.18
Previous HIV tests, n (%) 216 (89) 109 (90) 107 (88) 0.56 155 (81) 82 (84) 73 (78) 0.50
Partner HIV positive, n (%) 74 (31) 31 (25) 43 (36) 0.10 59 (31) 24 (25) 35 (38) 0.06
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
Defined as any sexual exposure excluding those with low risk.
Table 2. 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 (n¼243), OR (95% CI)
PEP discontinuations due to any cause in patients
who attended the day 1 visit (n¼191), OR (95% CI)a
Type of analysisa
univariate multivariate univariate multivariate
Randomization arm: ritonavir-boosted
lopinavir
1.2 (0.9–1.5), P¼0.17 1.9 (1.0–3.6), P50.04 2.1 (1.0–4.0), P50.03
Ageb
: 33 years old or younger 1.4 (1.1–1.8), P50.006 2.3 (1.1–4.8), P50.02 2.1 (1.2–4.0), P50.02 1.8 (0.9–3.6), P50.08
Gender: female 2.8 (1.2–6.7), P50.01 5.6 (1.3–23.8), P50.02 3.5 (1.2–9.9), P50.01 3.0 (1.0–9.0), P50.06
Race: non-Caucasian 2.3 (1.7–3.1), P<0.0001 3.1 (1.5–6.3), P50.002 2.6 (1.3–5.0), P50.004 2.6 (1.3–5.0), P50.006
Previous PEP: yes 1.8 (1.1–3.0), P50.01 3.7 (1.7–8.3), P<0.0001 0.8 (0.4–1.9), P¼0.66
High adherence to PEPc
: no 1.1 (1.0–1.2), P50.08
Presence of adverse events due to PEPc
: no 0.7 (0.2–1.9), P¼0.42
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
Population was split according to the median value.
c
Not measured in patients not attending the day 1 visit.
Leal et al.
4 of 7
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

5. events were resolved. There were 13 adverse events in four
patients who discontinued treatment as a result and who
attended the day 28 visit (n¼10 in the ritonavir-boosted lopinavir
and n¼3 in the raltegravir arm). Gastrointestinal toxicity was the
most frequently reported adverse event leading to PEP non-
completion in both arms.
Regarding laboratory abnormalities at day 28, a significant
increase in total cholesterol in the ritonavir-boosted lopinavir
arm was observed [mean (SEM) change in levels: 10 (5) versus
23 (3) mg/dL, P¼0.002]. No other significant differences between
groups were observed. When differences within each arm were
studied by comparing day 1 with day 28 values, a significant
increase in the levels of cholesterol [mean (SEM): 171 (5) to 182
(6), P¼0.03], triglycerides [mean (SEM): 99 (8) to 141(15),
P¼0.01], AST [mean (SEM): 25 (1) to 31(2), P¼0.01] and ALT
[mean (SEM): 25 (1) to 31(2), P¼0.02] were observed in the
ritonavir-boosted lopinavir arm, whereas no differences were
observed in the raltegravir arm. Laboratory abnormalities were
not the reason for PEP non-completion in any patient. All labora-
tory abnormalities were resolved by day 90.
Discussion
To our knowledge, this is the first randomized trial to compare an
integrase inhibitor with a PI in PEP. We assessed PEP outcome,
comparing ritonavir-boosted lopinavir versus raltegravir, both
with tenofovir disoproxil/emtricitabine as backbone, and found
no significant differences between arms regarding our primary
endpoint, PEP non-completion. On the other hand, younger indivi-
duals, women, non-Caucasians and those with previous PEP had a
significant and independent higher risk of PEP non-completion.
Since we had no information about individuals who did not attend
any follow-up visit, and no differences were found in non-
attendees between both treatment groups, we considered there
might be reasons other than antiretroviral regimen for these
losses. Consequently, we conducted another data analysis con-
sidering only those individuals who attended at least the day 1
follow-up visit. This showed that PEP non-completion and rates
of loss to follow-up, low adherence and adverse events were
significantly higher with ritonavir-boosted lopinavir.
This study was conducted concurrently with another one22
of similar characteristics and using the same methods, and
which compared ritonavir-boosted lopinavir versus the CCR5
inhibitor maraviroc, both with tenofovir disoproxil/emtricitabine
as backbone. In that study, PEP non-completion and adverse
events were significantly higher in patients allocated to tenofovir
disoproxil/emtricitabine plus ritonavir-boosted lopinavir, as com-
pared with tenofovir disoproxil/emtricitabine plus maraviroc.
Most data about tolerance and rate of discontinuation for
different PEP regimens have been reported in non-controlled
retrospective and prospective studies. Retrospective studies with
zidovudine/lamivudine plus ritonavir-boosted lopinavir show an
overall dropout rate of 35.5%, of which 17% was attributable to
side effects.23
These data are similar to those obtained by our
group in a previous clinical trial comparing PEP non-completion
at day 28 for ritonavir-boosted lopinavir versus atazanavir, both
with zidovudine/lamivudine as backbone. In that study, in which
255 individuals from six Spanish hospitals were randomized, PEP
non-completion at day 28 was similar between the two regimens
(36%) and the results showed that almost half of these failures
were due to side effects (16.5%).6
In a later, multicentre, observa-
tional, prospective non-controlled study, Tosini et al.7
found that
PEP with tenofovir disoproxil/emtricitabine plus ritonavir-boosted
lopinavir was associated with a 33.4% discontinuation rate, of
which 11.7% was attributable to adverse events. Despite these
PEP non-completion rates reported in different studies, PIs
became the recommended regimen in most guidelines, and
even following recent reviews the WHO and the European AIDS
Clinical Society still recommend them as the preferred regi-
men,9,13
particularly in resource-limited settings, given that
ritonavir-boosted lopinavir is cheaper than other antiretrovirals.
Our results in the ritonavir-boosted lopinavir arm for individuals
who attended at least the day 1 visit confirm these previous
findings. In these patients who attended at least on day 1, PEP
non-completion in the raltegravir arm was significantly lower
(20.4%) than almost any of the rates previously reported with
PI-containing regimens5,6,23
and similar to the rate observed in
a cohort using tenofovir disoproxil/emtricitabine plus raltegravir.24
These data suggest that raltegravir-containing regimens may be
better tolerated than are PIs for PEP.
One limitation of our study is the high proportion of patients lost
to follow-up: 18.5% did not attend the first scheduled visit, similar to
the 22% observed in our previous clinical trial and in other studies.5
In a recent meta-analysis, only 56.6% (95% CI: 50.9%–62.2%)
of people considered eligible for PEP completed the 28 day course.25
With the aim of minimizing this bias, a number of promising inter-
ventions have been described in the HIV treatment adherence lit-
erature, including treatment supporters, mobile phone messaging
and the use of fixed-dose combinations.26,27
Rabaud et al.28
con-
tacted by telephone any participant who did not attend follow-up
on day 14 and/or 28 after starting PEP, a strategy that reduced the
proportion lost to follow-up to 8%. We did not adopt any proactive
measure to improve retention. These data illustrate the high rate
of loss to follow-up along the PEP cascade of care and highlight
the difficulties of implementing correct PEP in the general popula-
tion; they also demonstrate the importance of engaging patients
and that more work is needed to transition patients from the ER to
regular care visits.
Another limitation of our study concerns low adherence.
Low adherence to PEP may compromise the effectiveness of
Table 3. Adverse events reported by exposed individuals coming at least
to the day 1 visit according to randomization arm
Ritonavir-boosted
lopinavir Raltegravir P
Number of exposed individuals 98 93
individuals with adverse
events, n (%)
72 (73) 56 (60) 0.007
Numberof total adverse events 185 116
gastrointestinala
, n (%) 106 (57) 67 (58) 0.93
neuropsychiatricb
, n (%) 26 (14) 27 (23) 0.04
asthenia, n (%) 33 (18) 21 (18) 0.95
Bold formatting represents significant P values.
a
Such as nausea, vomiting, diarrhoea, abdominal pain, flatulence, abdom-
inal distension and metallic taste.
b
Such as headache and insomnia.
Post-exposure prophylaxis for HIV
5 of 7
JAC
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

6. therapy.29
Based on the SMAQ we found that almost 50% of indi-
viduals on ritonavir-boosted lopinavir had low adherence,
whereas the rate was significantly lower in the raltegravir arm
(30.8%). Other authors have found low adherence to PEP with
tenofovir disoproxil/emtricitabine plus ritonavir-boosted lopinavir
in 30% of cases,7
although this was a longitudinal cohort study
and not a clinical trial and it is possible that its design may account
for differences in the results. Whatever the case, there is a need
to study different strategies for improving adherence to PEP,
with one possibility being the use of a single-tablet regimen.30
Factors associated with poor tolerance to PEP have not been
extensively studied. Here, we found that age, gender and ethnicity
were independently associated with PEP non-completion. There is
good evidence that women have a poorer tolerance to PEP,7,31
and better tolerated regimens should therefore be investigated
for this population. Contrary to what we expected, the presence
of adverse events related to PEP was not associated with non-
completion. A possible explanation for this could be that although
adverse events were frequently described by participants, most
were mild, well tolerated and easily resolved.
Finally, although adverse events and tolerance are likely to be
key issues when it comes to explaining the high drop-out rates
associated with PEP, the lack of differences between arms in the
proportion of patients who did not attend any visit after randomiza-
tion in the ER suggests that the reasons for this loss to follow-up
may be independent of medication. In fact, similar proportions
have been observed by our group and other authors.6,24,32
In summary, we observed an improvement in tolerance,
adherence and adverse events among patients on raltegravir as
compared with ritonavir-boosted lopinavir, both with tenofovir
disoproxil/emtricitabine as backbone. These results support
current recommendations regarding the use of raltegravir as a
preferred PEP regimen.
Acknowledgements
This study was presented at the Twenty-second Conference on
Retroviruses and Opportunistic Infections, Seattle, WA, USA (Abstract 959).
We would like to thank other members of the RALPEP Study Group for
their invaluable collaboration.
Members of the RALPEP Study Group
Lorna Leal, Agathe Leo´n, Berta Torres, Alexy Inciarte, Constanza Lucero, Jose´
L Blanco, Esteban Martı´nez, Josep Mallolas, Jose 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 M 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 MSDw
.
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.
Merck 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.
References
1 Tsai CC, Emau P, Follis KE et al. Effectiveness of postinoculation
(R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of
persistent simian immunodeficiency virus SIVmne infection depends critic-
ally on timing of initiation and duration of treatment. J Virol 1998; 72:
4265–73.
2 CDC. Case-control study of HIV seroconversion in health-care workers
after percutaneous exposure to HIV-infected blood—France, United
Kingdom, and United States, January 1988-August 1994. JAMA
1996; 275: 274–5.
3 Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant
transmission of human immunodeficiency virus type 1 with Zidovudine
treatment. N Engl J Med 1994; 331: 1174–80.
4 Mayer KH, Mimiaga MJ, Cohen D et al. Tenofovir DF plus lamivudine
or emtricitabine for nonoccupational postexposure prophylaxis (NPEP)
in a Boston Community Health Center. J Acquir Immune Defic Syndr
2008; 47: 494–9.
5 Jain S, Mayer KH. Practical guidance for nonoccupational postexposure
prophylaxis to prevent HIV infection: an editorial review. AIDS 2014; 28:
1545–54.
6 Diaz-Brito V, Leo´n A, Knobel H et al. Post-exposure prophylaxis for HIV
infection: a clinical trial comparing lopinavir/ritonavir versus atazanavir
each with zidovudine/lamivudine. Antivir Ther 2012; 17: 337–46.
7 Tosini W, Muller P, Prazuck T et al. Tolerability of HIV postexposure
prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet
formulation. AIDS 2010; 24: 2375–80.
8 WHO. Post-exposure Prophylaxis to Prevent HIV Infection: Joint WHO/ILO
Guidelines on Post-exposure Prophylaxis (PEP) to Prevent HIV Infection.
2007. http://www.who.int/hiv/topics/prophylaxis.
9 European AIDS Clinical Society (EACS). Guı´as clı´nicas. 2014. http://www.
eacsociety.org/files/guidlines-7.1-spanish.pdf.
10 Smith DK, Grohskopf LA, Black RJ et al. Antiretroviral postexposure
prophylaxis after sexual, injection-drug use, or other nonoccupational
exposure to HIV in the United States. MMWR Recomm Rep 2005; 54
(RR2): 1–20.
11 Quirino T, Niero F, Ricci E et al. HAART tolerability: postexposure prophy-
laxis in health care workers versus treatment in HIV-infected patients.
Antivir Ther 2000; 5: 195–7.
12 Siegfried N, Beanland RL, Ford N et al. Formulating the future research
agenda for postexposure prophylaxis for HIV: methodological challenges
and potential approaches. Clin Infect Dis 2015; 60 Suppl 3: S205–11.
13 WHO. Guidelines on Post-exposure Prophylaxis for HIV and the Use
of Co-trimoxazole Prophylaxis for HIV-related Infections Among
Adults, Adolescents and Children: Recommendations for a Public Health
Approach. 2015. http://www.who.int/hiv/topics/prophylaxis.
Leal et al.
6 of 7
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom

7. 14 Kuhar DT, Henderson DK, Struble K et al. Updated US Public Health
Service guidelines for the management of occupational exposures to
human immunodeficiency virus and recommendations for postexposure
prophylaxis. Infect Control Hosp Epidemiol 2013; 34: 875–92.
15 Gesida. Documento de Consenso sobre Profilaxis postexposicio´n ocupa-
cional y no ocupacional en relacio´n con el VIH, VHB y VHC en adultos y nin˜os.
2015. http://www.gesida-seimc.org/guias_clinicas.php.
16 Expert Advisory Group on AIDS (EAGA). Change to Recommended
Regimen for Post-exposure Prophylaxis. https://www.gov.uk.
17 Grupo de Consenso Espan˜ol sobre profilaxis postexposicio´n no
ocupacional al VIH. Recomendaciones para la profilaxis postexposicio´n
no ocupacional al VIH. Enferm Infecc Microbiol Clin 2002; 20: 391–400.
18 Knobel H, Alonso J, Casado JL et al. Validation of a simplified medica-
tion adherence questionnaire in a large cohort of HIV-infected patients:
the GEEMA Study. AIDS 2002; 16: 605–13.
19 Tuldra A, Ferrer, Fumaz C et al. Monitoring adherence to HIV therapy.
Arch Intern Med 1999; 159: 1376–7.
20 Martı´n J, Escobar I, Rubio R et al. Study of the validity of a questionnaire
to assess the adherence to therapy in patients infected by HIV. HIV Clin
Trials 2001; 2: 31–7.
21 WHO. A Practical Handbook on the Pharmacovigilance of Antiretroviral
Medicines. Geneva: WHO Press, 2009.
22 Leal L, Leo´n A, Torres B et al. A randomized clinical trial comparing
ritonavir-boosted lopinavir versus maraviroc each with tenofovir
plus emtricitabine for post-exposure prophylaxis for HIV infection.
J Antimicrob Chemother 2016; doi:10.1093/jac/dkw048.
23 Rabaud C, Bevilacqua S, Beguinot I et al. Tolerability of postexposure
prophylaxis with zidovudine, lamivudine, and nelfinavir for human
immunodeficiency virus infection. Clin Infect Dis 2001; 32: 1494–5.
24 Mayer KH, Mimiaga MJ, Gelman M et al. Raltegravir, tenofovir DF, and
emtricitabine for postexposure prophylaxis to prevent the sexual transmis-
sion of HIV. J Acquir Immune Defic Syndr 2012; 59: 354–9.
25 Ford N, Irvine C, Shubber Z et al. Adherence to HIV postexposure
prophylaxis: a systematic review and meta-analysis. AIDS 2014; 28:
2721–7.
26 Ba¨rnighausen T, Chaiyachati K, Chimbindi N et al. Interventions to
increase antiretroviral adherence in sub-Saharan Africa: a systematic
review of evaluation studies. Lancet Infect Dis 2011; 11: 942–51.
27 Ramjan R, Calmy A, Vitoria M et al. Systematic review and meta-
analysis: patient and programme impact of fixed-dose combination anti-
retroviral therapy. Trop Med Int Health 2014; 19: 501–13.
28 Rabaud C, Burty C, Grandidier M et al. Tolerability of postexposure
prophylaxis with the combination of zidovudine-lamivudine and lopinavir-
ritonavir for HIV infection. Clin Infect Dis 2005; 40: 303–5.
29 Roland ME, Neilands TB, Krone MR et al. Seroconversion following
nonoccupational postexposure prophylaxis against HIV. Clin Infect Dis
2005; 41: 1507–13.
30 Foster R, McAllister J, Read Tet al. Single-tablet emtricitabine-rilpivirine-
tenofovir as HIV postexposure prophylaxis in men who have sex with men.
Clin Infect Dis 2015; 61: 1336–41.
31 Luque A, Hulse S, Wang D et al. Assessment of adverse events
associated with antiretroviral regimens for postexposure prophylaxis for
occupational and nonoccupational exposures to prevent transmission of
human immunodeficiency virus. Infect Control Hosp Epidemiol 2007; 28:
695–701.
32 Chacko L, Ford N, Sbaiti M et al. Adherence to HIV post-exposure
prophylaxis in victims of sexual assault: a systematic review and
meta-analysis. Sex Transm Infect 2012; 88: 335–41.
Post-exposure prophylaxis for HIV
7 of 7
JAC
atOrtaDoguTeknikUniversityLibrary(ODTU)onMarch23,2016http://jac.oxfordjournals.org/Downloadedfrom