Low-Frequency Nevirapine Resistance at Multiple Sites May Predict Treatment Failure in Infants on Nevirapine-Based Treatment

Abstract

Background Resistance commonly arises in infants exposed to single-dose nevirapine (sdNVP) for prevention of mother to child transmission (PMTCT). While K103N and Y181C are common following sdNVP, multiple other mutations also confer NVP-resistance. It remains unclear whether specific NVP-resistance mutations or combinations of mutations predict virologic failure in infants when present at low frequencies prior to NVP-based treatment. Methods Twenty sdNVP-exposed infants who were subsequently treated with NVP-based highly active antiretroviral therapy (HAART) were examined. Pre-treatment plasma samples were tested for the presence of NVP-resistance mutations by allele-specific PCR (ASPCR) for K103N and Y181C and ultra-deep pyrosequencing (UDPS) for all primary NVP mutations. Viral levels were determined every 3 months for up to 24months on NVP-HAART. Cox proportional hazard models were used to determine correlates of viral failure. Results The NVP resistance mutations K103N or Y181C were detected in pre-treatment plasma samples in 6 infants by ASPCR. NVP resistance at these or other sites was detectable by UDPS in 10 out of 20 infants tested. Virologic failure occurred in 50% of infants with any NVP resistance mutations detected, while only 20% of infants without resistance experienced viral failure, but the difference was not significant (p=0.19). An increase in the number of NVP resistance mutations detectable by UDPS in an infant was significantly associated with an increased risk of virologic failure (HR=1.79 (95%CI: 1.07, 2.99), p=0.027). Conclusions Low frequencies of multiple NVP resistance mutations, in addition to K103N and Y181C, present in infants before NVP-based treatment may predict treatment outcome.

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

“…Indeed high-sensitivity methods for measurement of drug resistance were not used in this study. However the usefulness of using high-sensitivity methods over consensus sequencing to predict virological failure in children is unclear [12, 13]. …”

Resistance to Reverse Transcriptase Inhibitors Used in the Treatment and Prevention of HIV-1 Infection

“…Follow-up analyses revealed that participants who harbored low-frequencies of K103N or Y181C (as detected by allele specific PCR assay), had > 3 times the risk of virologic failure compared to women without these mutations [34]. The association between NNRTI-resistant minority variants and treatment failure has also been documented in several other studies of women and children exposed to sdNVP [35–38]. …”

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy

“…The pre-randomization cohort has been described[21]. Among infants enrolled prior to ART, pre-ART mortality was high despite short median time to ART (2 weeks from diagnosis)[20]. Of 75 children who completed 2-year ART, 29 did not meet randomization eligibility criteria or had evidence of non-adherence, treatment switch or unplanned TI; 4 children were pending randomization when the DSMB recommended stopping the study.…”

“…HIV RNA measurements were conducted at the Fred Hutchinson Cancer Research Center in Seattle, using the Gen-Probe HIV-1 RNA assay (Gen Probe, San Diego CA). Genotypic resistance testing was conducted in Nairobi using a population-based Sanger sequencing method described previously[20]. Interpretation of the sequences conferring resistance utilized the Stanford University HIV Drug resistance Database (http://hivdb.stanford.edu/).…”