Use of Maraviroc in HIV-1-Infected Paediatric Patients in Clinical

Use of Maraviroc in HIV-1-Infected Paediatric Patients in Clinical

Use of Maraviroc in HIV-1-Infected Paediatric Patients in Clinical Practice
950
C. Palladino1, ML. Navarro Gomez2, P. Soler-Palacín3, MI. González-Tomé4, S. J. de Ory5, M. Espiau3,JA. León-Leal6, C. Fortuny7, V. Briz8
the CoRISpe working group
1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; 2 Servicio de Pediatría, Hospital General Universitario ‘Gregorio Marañón‘, Madrid, Spain; 3 Unitat de Patologia Infecciosa i
Immunodeficiències de Pediatria, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 4 Servicio de Infecciosas Pediátricas, Hospital Universitario ‘Doce de Octubre’, Madrid, Spain; 5 Laboratorio InmunoBiología Molecular, Hospital General
Universitario ‘Gregorio Marañón‘. Instituto de Investigación Sanitaria ‘Gregorio Marañón‘ (IiSGM), Madrid, Spain. Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain; 6 Unidad Medicina Interna
Pediátrica, Hospital Infantil Universitario ‘Virgen del Rocío‘, Seville, Spain; 7 Unitat d´Infectologia, Servei de Pediatria; Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain; 8 Viral Infection and Immunity Lab. Area of
Molecular Pathology. National Center for Microbiology, Madrid, Spain.
Background
New potent therapeutic options are needed
for HIV-1-infected paediatric patients who
are treatment experienced and harbour highly
drug-resistant viruses.
Maraviroc (MVC), the first CCR5-antagonist
approved to treat adults with R5-variants, is
not yet authorised in paediatric patients (1-3).
Table 1.
baseline.
Characteristics
Baseline characteristics
Age in years;
median (IQR)
Gender, girls;
n (%)
Ethnicity, caucasian;
HIV subtype;
Objective
To evaluate the effectiveness, safety and
tolerability of MVC-based salvage therapy
outside clinical trials in HIV-1-vertically
infected children (2–12yrs old) and adolescents
(13-19yrs old).
Patients & Methods
Multicenter retrospective study of 20 HIV-1
vertically-infected paediatric patients (≤19yrs)
ART-experienced and who initiated a MVCbased therapy.
Individuals were monitored from baseline
(MVC initiation date) until the administrative
censoring date (May 31, 2014) or MVC
discontinuation if occurred.
Immunological, virological and clinical status at
baseline and during follow-up was analysed
every 3-6 months.
Viral tropism was determined by phenotypic
assays (Trocai and Trofile®) or by the
genotypic assay geno2pheno.
MVC was administered in tablet formulation
and doses ranged from 100-300 mg twice daily
for children and 150-600 mg twice daily for
adolescents, according to body weight and comedications.
the
patients
at
N=20
15.1 (12.9-16.3)
n (%)
Table 2. Outcome of the use of MVC in the study
population.
Outcome
N=20
Weeks of MVC regimen;
Responders (HIV-1 RNA <50 copies/mL)
16 (80%)
Insufficient HIV-1 RNA response
4 (20.0)
HIV-1 RNA log copies/mL;
17 (85.0)
CD4 count, cells/µL;
Unknown
3 (15.0)
CD4%, cells/µL;
Adherence,
n (%)
R5
16 (80.0)
D/M
1 (5.0)
Unknown
3 (15.0)
HIV-1 RNA log copies/mL;
CD4 count, cells/µL;
median (IQR)
median (IQR)
Immune category,
4.0 (3.2-4.9)
382 (191-662)
22.0 (14.4-28.7)
median (IQR)
n (%)
≥500 cells/µL
9 (45.0)
200-499 cells/µL
6 (30.0)
<200 cells/µL
5 (25.0)
Clinical category C;
10 (50.0)
n (%)
Patients exposed to mono- and/or dualtherapy prior MVC initiation; n (%)
115.6 (25.1–198.2)
17 (85.0)
n (%)
CD4%, cells/µL;
median (IQR)
13 (65.0)
B
HIV-1 tropism;
MVC is currently under evaluation in an openlabel, non-comparative trial (A4001031) in
CCR5-tropic
HIV-1-infected
antiretroviral
therapy (ART)-experienced patients aged 2-17
years.
of
15 (75.0)
Years of HAART prior MVC;
median (IQR)
10.7 (9.4-12.8)
HAART regimens prior MVC;
median (IQR)
3.0 (2.3-4.8)
Legend: IQR, interquartile range; R5, CCR5-tropic variants; D/M, dual/mixed-tropic variants;
HAART, highly active antiretroviral therapy; MVC, maraviroc.
Results
At baseline, median viral load (VL) was 3.8 log
and 4.1 log in children and adolescents; median
CD4 cell was 25% and 22%, respectively (Tab1).
Genotypic resistance profile showed a median of
3 major PI mutations, 2 NNRTI mutations, and 5
NRTI mutations. 10 (53%) patients showed highlevel resistance to ≥5 NRTIs and 10 (53%)
patients had high-level resistance to NRTIs,
NNRTIs and PIs.
At least 1 fully active drug was prescribed to
18 (95%) patients as backbone regimen, of whom
17 (94%) received MVC with one or more new
drugs (DRV/r, ETR, RLT).
median (IQR)
median (IQR) (N=19)
median (IQR) (N=18)
Mild adverse events related
therapy were reported.
27.3 (23.2-32.1)
n (%)
4 (20.0)
Good
9 (45.0)
Moderate
2 (10.0)
Poor
5 (25.0)
n (%)
Hypercholesterolemia
(>170mg/dl)
9 (45.0)
Hypertriglyceridemia
(>150mg/dl)
12 (60.0)
(<45mg/dl)
MVC-based
2 adolescents died and 8 subjects interrupted
MVC (Tab3).
Table 3. Cause of MVC interruption and underlying
cause of death.
Cause of MVC interruption
N=20
Death
2 (10.0)
Simplification
3 (15.0)
Virological failure
1 (5.0)
X4 or D/M variants emergence
HDL reduction (N=12)
to
1.7 (1.6-3.8)
558 (429-880)
Complete
Laboratory data,
Immunological improvement was observed in
14/20 patients (11 responders and 3 nonresponders) with median increase of 275 CD4
cells/µl (IQR:135–500).
1 (8.3)
ALT increase (N=19)*
4 (21.1)
AST increase (N=17)*
--
Legend: X4, CXCR4-tropic variants; D/M, dual/mixed-tropic variants; HDL, high-density lipoprotein;
ALT, alanine aminotransferase; AST, aspartate aminotransferase; MVC, maraviroc.* ALT and AST
increases
were
classified
according
to
the
following
references:
http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l40_c_met_aspartate_aminotransferase.pdf and
http://www.cdc.gov/nchs/data/nhanes/nhanes_05_06/biopro_d_met_alt.pdf
Reasons for MVC initiation: virological failure
and/or resistance mutations to previous regimens
(n=14; 70%); PI-associated lipodystrophy (n=1;
5%); simplification (n=1; 5%); improve adherence
and ART toxicities (n=1; 5%); ART toxicity or
drug interactions (n=2; 10%); ART intensification
(n=1; 5%).
16 (80%) patients reached undetectable VL <50
cop/ml (uVL) [(median at 13 weeks, (5–35)] with a
median decrease in VL from baseline of 1.7 log
(Tab2). 12/16 (75%) maintained uVL for a median
of 105 weeks (IQR:44–208) of which 9/12 (75%)
patients maintained uVL until the end of the
study for a median of 132 (50-230) weeks.
Among patients with confirmed R5-tropism,
14/16 (88%) reached uVL [(median at 18.1
weeks, (IQR:5.5–38.5)] with a median VL
decrease of 1.7 log; 11/16 (69%) maintained uVL
for 120 weeks (IQR:49-228).
Poor adherence
3 (15.0)
1 (5.0)
Cause of death
N=2
Hypertensive cerebral haemorrhage
1
Wasting syndrome
1
Legend: X4, CXCR4-tropic variants; D/M, dual/mixed-tropic variants; MVC, maraviroc.
Conclusions
MVC is useful as a salvage therapy in paediatric
patients with confirmed R5 tropism and extensive
resistance
profile,
leading
to
maintained
virological suppression in up to 88% of the study
population.
MVC appears to have a favourable safety
profile. The likelihood of the treatment’s success
might increase when MVC is combined with other
active drugs.
Acknowledgments
To the patients and
the collaborating centers for their participation.
References
1.FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/
2007/022128lbl.pdf. 2007.
2.EMA. http://www.ema.europa.eu/docs/en_GB/document_
library/EPAR_Product_Information/human/000811/WC5000221
90.pdf. 2007.
3.Gulick RM, et al. N Engl J Med 2008.
Co-responding authors: [email protected]
22nd Conference On Retroviruses And Opportunistic Infections, Seattle; February 23-26, 2015
[email protected]