Poster santoro icar rilpivirina
Low Prevalence of Primary Rilpivirine Mutations in NNRTI-Naïve Patients is
Found in B and Most Frequent Non-B HIV-1 Subtypes in Italy
M.M. Santoro1
, C. Alteri1, A. Bertoli1,2, C. Gori3, V. Borghi4, L. Fabeni3, I. Fanti5, N. Orchi6, C. Pinnetti7, C. Tommasi7, N. Cesta8, E. Girardi6, G.
D'Offizi7, M. Giuliani9, A. D'Arminio Monforte10, M. Andreoni8,11, C. Mussini4, A. Antinori7, C.F. Perno1,2,3, F. Ceccherini-Silberstein1
1University of Rome Tor Vergata, Experimental Medicine and Surgery, Rome, Italy; 2University Hospital Tor Vergata, Molecular Virology Unit, Rome, Italy; 3L. Spallanzani Hospital, Antiretroviral Therapy Monitoring Unit,Rome, Italy; 4Polyclinic of Modena, Clinic of Infectious Diseases, Modena, Italy; 5Catholic University, Institute of Clinical Infectious Diseases, Rome, Italy; 6L. Spallanzani Hospital, Epidemiology, Rome, Italy; 7L. Spallanzani
Hospital, Division of Infectious Diseases, Rome, Italy; 8University Hospital Tor Vergata, Infectious Diseases Division, Rome, Italy; 9San Gallicano Hospital, Infectious Dermatology, Rome, Italy; 10San Paolo Hospital for theICONA foundation, Health Sciences, Milan, Italy; 11University of Rome Tor Vergata, Public Health and Cellular Biology, Rome, Italy.
Background
Prevalence of RRMs in drug-naïve, NNRTI-naïve and
Evaluation of primary RRMs in subtypes B, C, F
NNRTI-treated patients
and CRF02_AG
•Rilpivirine (RPV) is a second generation non nucleoside reverse
transcriptase inhibitor (NNRTI) recently approved for HIV-1 treatment.
•The activity of this antiretroviral is against a broad spectrum of wild
type and first-generation NNRTI-resistant HIV-1 viruses.
•Several NNRTI mutations have been already associated with
E138K+M184I was commonly detected in patients with virologic failure
Multiple-hypothesis testing = Benjamini-Hochberg method.
Objective
After correction for multiple-hypothesis testing,
only the primary
RRM E138G was present
with a significant prevalence within
Primary RRMs
Other potential RRMs
Here, we evaluated the RPV-resistance according the treatment and
the different subtypes. Indeed, this RRM was
mostly found in
-The
E138A was the most common primary RRM both in drug-naïve
the overall F-subtype population in comparison to other
subtype in the most common HIV-1 subtypes in Italy (B, C, F, and
(
4.5%) and NNRTI-naïve (
6%) patients.
subtypes (
P=0.001). Similar results were obtained by analyzing
Its prevalence was similar in NNRTI-treated patients (
5.2%).
-Among the other potential RRMs,
V179I was the most common
Materials and Methods
mutation found in all 3 groups of patients, followed by the mutations
V90I and
V106I.
Analysis performed on plasma samples of
7,444 RPV-naïve patients
-Several RRMs (such as
K101T,
E138K/R,
V179L,
Y181I/V,
Y188C,
infected by the following
HIV-1 subtypes:
G190E,
F227C,
M230I) were with a prevalence ≤1% or completely
•
B (N=
6,287)
•
CRF02_AG (N=
547)
-Of interest,
all RRMs with high phenotypic resistance (as
•
C (N=
332)
K101E/P,
E138K/Q/R,
Y181C/I/V,
Y188L,
F227C,
M230L) were
•
F (N=
278)
absent or with a prevalence <1% in drug-naïve patients.
These patients belonged to 3 categories:
1) Drug-naïve (N=
4,974)
Prevalence of RRMs in efavirenz and nevirapine-
The
proportion of patients with at least 1 RRM was
similar in
2) HAART failing patients, never exposed to NNRTIs
the
different subtypes analyzed, while a
significantly higher
failing patients
(
NNRTI-naïve; N=
1,211)
proportion of patients with at least 2 RRMs was observed
in
3) NNRTI failing patients (
NNRTI-treated; N=
1,259)
C subtype in comparison to subtypes B, F and CRF02_AG
a) 664 efavirenz-treated
b) 578 nevirapine-treated
Factors related to the presence of at least 1 and 2 RMMs
c) 17 etravirine-treated
in multivariable logistic regression models
According to treatment and subtype, we analyzed the following primary
By multivariable analysis, the
presence of ≥1 primary RRM or
RPV-resistance mutations (RRMs): L100I, K101E/P, E138A/G/K/Q/R,
≥2 primary RMMs was
associated with
a high viremia at the
moment of genotypic test and
the NNRTI-usage, but
not with
(
http://hivdb.stanford.edu/, Johnson et al., Top HIV Med 2013).
the subtype.
To identify patterns associated with RPV-resistance, other potential
At least 1 mutation
At least 2 mutations
RRMs V90I-K10IT-V106A/I/M-V179I-Y188C/H, as well as the NNRTI-
mutation K103N and the emtricitabine-lamivudine mutations M184I/V
In addition, Stanford-resistance interpretation algorithm was used to
evaluate the RPV-resistance-score.
Logistic-regression
According to NNRTI-usage, the mutations
L100I,
K101P,
G190E
were
more frequently found in
efavirenz-failing patients than in
nevirapine-failing patients.
Conversely,
Y181C,
G190A, H221Y were more prevalent in
Number of RRMs according to the treatment status
nevirapine than in efavirenz-failures.
Viremia at the time of GRTb
<0.001
0.007
Patients with
at least 1 primary RRM and
at least 2 primary
CD4 at time of GRTc
0.018
RRMs were
mostly found in NNRTI treated patients than in
Evaluation of RRMs patterns
Therapy status
NNRTI-naïve or drug naïve patients (
P<0.001).
NNRTI-treated
-
No patient carried the typical RPV-failure pattern
E138K+M184I
NRTI-naïve
<0.001
0.11 <0.001
-
7 patients carried the
E138K+M184V:
Drug-naïve
<0.001
0.06 <0.001
-
4 NNRTI-treated (0.3%)
In red boldface are reported the independent factors statically significant in multivariable
-
3 NNRTI-naïve (0.3%)
analysis. a Per 5 year increase. b Per 1 log
increase. c per 50 cells increase. GRT: genotypic
Covariation analysis showed that
RRMs L100I, V90I, and
Using the Stanford algorithm,
about 90% of the overall samples
K101T are frequently found in pairs…
analyzed was
susceptible to RPV,
regardless of subtype.
Covariation
Frequency
Frequency
Mutation
Mutation
frequency
The
most part of patients analyzed had only one primary RRM.
A
consistent proportion of NNRTI-treated patients had
also 2 or
were calculated by Chi-square test (based on a 2
3 primary RRMs.
by 3 contingency table)according to the subtype,
According to treatment status, samples susceptible to RPV were
a The frequency was determined in 2,470 HIV-1 B isolates from NNRTI-naïve and NNRTI-
98.2% in
drug-naïve patients,
95.5% in
NNRTI-naïve patients
treated patients.
b Positive correlations with phi >0.10 are shown.
c All
p values for covariation
were significant at a false discovery rate of 0.05 following correction for multiple-hypothesis
and
54.5% in
patients failing to NNRTIs (
efavirenz:
60.8%;
testing (Benjamini-Hochberg method).
nevirapine:
47.8%;
etravirine:
35.3%).
…and also in specific clusters!
Conclusions
Among NNRTI-treated patients,
the highest presence of at least 1
•
Analyzing more than 7,000 HIV-1 infected patients naïve to
primary RRM or at least 2 primary RRMs was
found in patients
RPV,
resistance to this NNRTI is found
with very low
treated with etravirine (ETR), followed by nevirapine (NVP) and
prevalence in drug-naïve and
NNRTI-naïve patients, while it
is
finally by efavirenz (EFV) (
P<0.001).
found in about half of NNRTI failing patients,
mainly in those
treated
with etravirine or nevirapine rather than with efavirenz.
At least 2 RRMs
•
Different HIV-1 subtypes do not significantly influence the
presence of RPV-resistance mutations.
Acknowledgments
Dendrogram was obtained using average linkage hierarchical clustering. At each edge bootstrap
Source: http://www.fondazioneicona.org/_new/download/home/icar2013/Santoro.pdf
HOF VAN CLEVE’S GENERAL TERMS AND CONDITIONS FOR DISTANCE SELLING. 1. Hof van Cleve’s contact details. Hof van Cleve Riemegemstraat 1 BE-9770 Kruishoutem RLP / VAT-number: BE 0480.498.705 Hereafter named “Hof van Cleve”. 2. Content and terms of the agreement §1 These general terms and conditions are applicable to every offer of Hof van Cleve and to every distance agreement conclude
PATIENT INFORMATION A publication of Jackson-Madison County General Hospital Surgical Services Tonsillectomy You are scheduled to have a Tonsillectomy (removal of the tonsils from the throat). The purpose of this handout is to help you know how to prepare for this surgery and what to expect during your surgery. It is the hope of the surgery staff that you will feel that you receive very