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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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Non-nucleoside reverse transcriptase inhibitors (NNRTI) mutation profiles.Profiles associated with failure to NNRTIs are depicted in white, profiles associated with failure to non-NNRTI regimens are depicted in grey. The numbers represent percentages.
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pone-0097067-g001: Non-nucleoside reverse transcriptase inhibitors (NNRTI) mutation profiles.Profiles associated with failure to NNRTIs are depicted in white, profiles associated with failure to non-NNRTI regimens are depicted in grey. The numbers represent percentages.

Mentions: A detailed analysis of mutations associated with NNRTI resistance stratified according to a NNRTI or non-NNRTI-containing regimen, is depicted in Figure 1 and 2. A total of 265 children (74.9%) had been exposed to EFV or NVP, including 8 children who received a LPV/r-based regimen at time of resistance testing. The most common NNRTI mutation in this group was K103N (n = 152, 57.4%) followed by V106M (n = 105, 39.6%), P225H (n = 42, 15.8%) and V179D (n = 29, 10.9%, Figure 1). The Y181C mutation appeared more frequently among children without recorded NNRTI-exposure (9.0% vs 6.4%), this trend was however not statistically significant (p = 0.4728). The presence of other NNRTI-mutations such as K103N (11.2%) in the non-NNRTI group indicates that non-disclosed NNRTI-exposure might have taken place in some of these patients, most likely as a result of PMTCT. Predictably, most viruses from NNRTI-exposed children showed high-level resistance to NVP (96.6%) and EFV (94.3%). Of note, more than a third of the children in this group showed reduced susceptibility to 2nd-generation NNRTIs such as etravirine (37.3%) and rilpivirine (44.2%, Figure 2).


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)

Non-nucleoside reverse transcriptase inhibitors (NNRTI) mutation profiles.Profiles associated with failure to NNRTIs are depicted in white, profiles associated with failure to non-NNRTI 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-g001: Non-nucleoside reverse transcriptase inhibitors (NNRTI) mutation profiles.Profiles associated with failure to NNRTIs are depicted in white, profiles associated with failure to non-NNRTI regimens are depicted in grey. The numbers represent percentages.
Mentions: A detailed analysis of mutations associated with NNRTI resistance stratified according to a NNRTI or non-NNRTI-containing regimen, is depicted in Figure 1 and 2. A total of 265 children (74.9%) had been exposed to EFV or NVP, including 8 children who received a LPV/r-based regimen at time of resistance testing. The most common NNRTI mutation in this group was K103N (n = 152, 57.4%) followed by V106M (n = 105, 39.6%), P225H (n = 42, 15.8%) and V179D (n = 29, 10.9%, Figure 1). The Y181C mutation appeared more frequently among children without recorded NNRTI-exposure (9.0% vs 6.4%), this trend was however not statistically significant (p = 0.4728). The presence of other NNRTI-mutations such as K103N (11.2%) in the non-NNRTI group indicates that non-disclosed NNRTI-exposure might have taken place in some of these patients, most likely as a result of PMTCT. Predictably, most viruses from NNRTI-exposed children showed high-level resistance to NVP (96.6%) and EFV (94.3%). Of note, more than a third of the children in this group showed reduced susceptibility to 2nd-generation NNRTIs such as etravirine (37.3%) and rilpivirine (44.2%, Figure 2).

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