High-Level Cross-Resistance to ddI Observed in South African Children Failing an ABC- or d4T-Based 1st-Line Regimen

Author: Jennifer Giandhari and Joanna Ledwaba - 2014-07-25

The current South African guidelines for HIV-1 infected paediatric patients recommend the use of Abacavir (ABC) and Lamivudine (3TC) in the 1st-line regimen and Didanosine (ddI) and Zidovudine (AZT) in the 2nd-line regimen following virological failure. This study aimed to assess the levels of cross-resistance to ddI following ABC and Stavudine (d4T)-containing 1st-line regimen in children.

Figure 1. Prevalence of resistance to Nucleoside/tide Reverse Transcriptase Inhibitors. Prevalence of susceptible (S, solid bars), intermediate (I, striped bars) or high-level resistance (R, dotted bars) to nucleoside reverse transcriptase inhibitors (NRTIs) after exposure to an ABC containing regimen (n = 81, white) or d4T containing regimen (n = 273, grey). The numbers represent percentages. Abbreviations: ABC: abacavir, TDF: tenofovir, ddI: didanosine, d4T: stavudine, 3TC: lamivudine, FTC: emtricitabine, AZT: zidovudine.

A group of researchers from the University of Witwaterstrand analysed a retrospective dataset from HIV-1 infected children failing either ABC (n= 81) or d4T (n= 273). It was shown that children who were administered ABC had high levels of resistance (n=50, 61.7%) while more children remained susceptible to d4T, irrespective of the exposure to ABC (n=63, 77.8%) or d4T (n=204, 75.5%), as illustrated on the figure below. In addition, a large number of children remained susceptible to AZT after receiving ABC (n=72, 88.9%) and d4T (n=217, 79.5%). The ABC group showed high levels of cross resistance to ddI (n=49, 60.5%) compared to d4T (n=25, 9.2%), and the cross-resistance to ddI was attributed to mutation L74V/I (n=44). K65R mutation was more apparent in patients failing ABC (n=10, 12.3%) versus d4T (n=5, 1.8%). Of 108 PI-experienced children, 52 (47.7%) showed no resistance to PIs. A significant number of children (n=265) received NNRTI (EFV or NVP) and K103N (n=152, 57.4%) was the most common mutation in this drug class.

This study had a significant impact on the change of ddI to AZT in the 2nd-line following ABC or d4T treatment. Going forward, this study proves that it is necessary to take into consideration the effects of mutations on new antiretroviral drugs especially in paediatric patients who have very limited treatment options. This will help to increase effectiveness and improve longevity of their regimens.


High-Level Cross-Resistance to Didanosine Observed in South African Children Failing an Abacavir- or Stavudine-Based 1st-Line Regimen. Kim Steegen, Leon Levin, Irene Ketseoglou, Michelle Bronze, Maria A.Papathanasopoulos, Sergio Carmona, Wendy Stevens. PLoS ONE 9(5): e97067. doi:10.1371/journal.pone.0097067


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