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. SpallanzaniHospital, 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
-Of interest, all RRMs with high phenotypic resistance (as
•C (N=332) K101E/P, E138K/Q/R, Y181C/I/V, Y188L, F227C, M230L) were
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
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