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High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen.

Steegen K, Levin L, Ketseoglou I, Bronze M, Papathanasopoulos MA, Carmona S, Stevens W - PLoS ONE (2014)

Bottom Line: The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations.The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.

ABSTRACT

Background: The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.

Methods: A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.

Results: Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).

Conclusion: Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

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Related in: MedlinePlus

Protease Inhibitor mutation profiles.Mutation profiles associated with failure to PIs are depicted in white, mutation profiles associated with failure to non-PI-based regimens are depicted in grey. The numbers represent percentages.
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pone-0097067-g003: Protease Inhibitor mutation profiles.Mutation profiles associated with failure to PIs are depicted in white, mutation profiles associated with failure to non-PI-based regimens are depicted in grey. The numbers represent percentages.

Mentions: A detailed analysis of mutations associated with PI resistance, stratified according to a PI or non-PI-containing regimen, is depicted in Figure 3 and 4. Most children (n = 245, 69.2%) did not have any documented exposure to protease inhibitors, hence 80.8% (n = 198) did not show any level of resistance to this drug class (Figure 3). Of the children without documented PI-exposure, 44 (18.0%) children showed reduced susceptibility to boosted nelfinavir (NFV/r) (Figure 4), caused by polymorphism T74S mutation in all but one child (Figure 3).This T74S mutation is a known subtype C polymorphism. Reduced susceptibility to NFV/r in the remaining patient was caused by N88D. A further three children, without documented PI-exposure, presented with medium to extensive PI resistance. One patient showed intermediate resistance to 4 PIs, including LPV/r. Another patient presented with high-level resistance to 4 PIs, including LPV/r, as well as intermediate resistance to 3 PIs. The third patient showed high-level resistance to all PIs except boosted tipranavir (intermediate resistance) and boosted darunavir (susceptible). The resistance profiles of these three patients indicate either undisclosed PI-exposure or transmitted drug resistance.


High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen.

Steegen K, Levin L, Ketseoglou I, Bronze M, Papathanasopoulos MA, Carmona S, Stevens W - PLoS ONE (2014)

Protease Inhibitor mutation profiles.Mutation profiles associated with failure to PIs are depicted in white, mutation profiles associated with failure to non-PI-based regimens are depicted in grey. The numbers represent percentages.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016228&req=5

pone-0097067-g003: Protease Inhibitor mutation profiles.Mutation profiles associated with failure to PIs are depicted in white, mutation profiles associated with failure to non-PI-based regimens are depicted in grey. The numbers represent percentages.
Mentions: A detailed analysis of mutations associated with PI resistance, stratified according to a PI or non-PI-containing regimen, is depicted in Figure 3 and 4. Most children (n = 245, 69.2%) did not have any documented exposure to protease inhibitors, hence 80.8% (n = 198) did not show any level of resistance to this drug class (Figure 3). Of the children without documented PI-exposure, 44 (18.0%) children showed reduced susceptibility to boosted nelfinavir (NFV/r) (Figure 4), caused by polymorphism T74S mutation in all but one child (Figure 3).This T74S mutation is a known subtype C polymorphism. Reduced susceptibility to NFV/r in the remaining patient was caused by N88D. A further three children, without documented PI-exposure, presented with medium to extensive PI resistance. One patient showed intermediate resistance to 4 PIs, including LPV/r. Another patient presented with high-level resistance to 4 PIs, including LPV/r, as well as intermediate resistance to 3 PIs. The third patient showed high-level resistance to all PIs except boosted tipranavir (intermediate resistance) and boosted darunavir (susceptible). The resistance profiles of these three patients indicate either undisclosed PI-exposure or transmitted drug resistance.

Bottom Line: The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations.The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.

ABSTRACT

Background: The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.

Methods: A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.

Results: Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).

Conclusion: Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

Show MeSH
Related in: MedlinePlus