Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.
The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.
*Division of Infection and Immunity, University College London, London United Kingdom; †Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ‡Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; §Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; ||HJF-DAIDS, a Division of the Henry M Jackson Foundation for the Advancement of Military Medicine Inc, Contractor, NIAID, NIH, Department of Health and Human Services, Bethesda, MD; ¶Anova Health Institute, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; and #Africa Centre for Health and Population Studies, University of KwaZulu Natal.
Camille Marie
CM
Lange
Stéphane
S
Hué
Avy
A
Violari
Mark
M
Cotton
Diana
D
Gibb
Abdel
A
Babiker
Kennedy
K
Otwombe
Ravindre
R
Panchia
Els
E
Dobbels
Patrick
P
Jean-Philippe
James A
JA
McIntyre
Deenan
D
Pillay
Ravindra Kumar
RK
Gupta
D002675:Child, Preschool; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D016679:Genome, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load
D017320:HIV Protease Inhibitors