Prevalence and effect of pre-treatment drug resistance on the virological response to antiretroviral treatment initiated in HIV-infected children - a EuroCoord-CHAIN-EPPICC joint project.
Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.



HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.



Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1-10.1), CD4 cell count 297 cells/mm3(98-639), and HIV-RNA 5.2 log10copies/mL (4.7-5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5-10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4-23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2-54.8) versus 19.4 % (15.9-23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82-0.95; P < 0.001).



PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
IRD UMI 174 - PHPT-Faculty of Associated Medical Sciences, Chiang Mai University, 110, Intrawarorot Road, Sripoom, Muang, Chiang Mai, 50200, Thailand. Nicole.Ngo-Giang-Huong@phpt.org.|Harvard T.H. Chan School of Public Health, Boston, USA. Nicole.Ngo-Giang-Huong@phpt.org.
Nicole
0000-0001-8950-3234
N
Ngo-Giang-Huong
Univ. Bordeaux, ISPED; INSERM, Centre INSERM U1219; CHU de Bordeaux, Pole de Sante Publique, F-33000, Bordeaux, France.
Linda
L
Wittkop
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Ali
A
Judd
Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Peter
P
Reiss
Hôpital Saint-Pierre, Brussel, Belgium.
Tessa
T
Goetghebuer
"Dr. Victor Babes" Hospital for Infectious and Tropical Diseases, Bucharest, Romania.
Dan
D
Duiculescu
Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain.
Antoni
A
Noguera-Julian
Medical University of Warsaw, Warsaw, Poland.
Magdalena
M
Marczynska
University of Padua, Padua, Italy.
Carlo
C
Giacquinto
"Dr. Victor Babes" Hospital for Infectious and Tropical Diseases, Bucharest, Romania.
Luminita
L
Ene
University Hospital of Getafe, Madrid, Spain.
Jose T
JT
Ramos
Lausanne University Hospital, Lausanne, Switzerland.
Cristina
C
Cellerai
University of Basel, Basel, Switzerland.
Thomas
T
Klimkait
Saint-Luc, Brussels, Belgium.
Benedicte
B
Brichard
Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Valerius
University College London, London, UK.
Caroline
C
Sabin
Hospital de Sierrallana, Torrelavega, Spain.
Ramon
R
Teira
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Niels
N
Obel
University Clinic Frankfurt, Frankfurt, Germany.
Christoph
C
Stephan
AIDS Reference Center, CHU Saint-Pierre, Brussels, Belgium.
Stéphane
S
de Wit
University College London, Institute of Child Health, London, UK.
Claire
C
Thorne
Medical Research Council Clinical Trials Unit, London, UK.
Diana
D
Gibb
Bordeaux RCC, INSERM, U897, Bordeaux, France.
Christine
C
Schwimmer
Copenhagen RCC, Rigshospitalet, Copenhagen, Denmark.
Maria Athena
MA
Campbell
University College London, London, UK.
Deenan
D
Pillay
IRD UMI 174 - PHPT-Faculty of Associated Medical Sciences, Chiang Mai University, 110, Intrawarorot Road, Sripoom, Muang, Chiang Mai, 50200, Thailand.
Marc
M
Lallemant
D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors
Children; First-line combination antiretroviral therapy; HIV; Pre-treatment drug resistance mutations; Virological failure