Global survey shows high frequency of resistance after first-line ART failure in children

90% of HIV-infected children in the resource-poor regions of Africa, Asia and Latin America had at least one drug resistance mutation after failure of first-line ART, Dutch researchers report in a systematic review published in this month’s Lancet Infectious Diseases.

 Specific drug-class resistance rates were 88%, 80% and 54% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), respectively.

In spite of geographical and virological differences the rates are similar to those found in children in Europe, Kim Sigaloff and colleagues note.

The researchers say that the findings highlight the need for ongoing development of formulations of new antiretroviral drugs that are suitable for children to take.

Children infected vertically are especially vulnerable. Disease progression and death is rapid; over 50% of children who do not get ART will die before they reach two years of age. In 2008 an estimated 38% of children in need of ART were getting it.

Revised guidelines which recommend that all HIV-positive children under two years of age start ART regardless of clinical or immunological criteria are likely to increase these numbers considerably.

A poor virological response, common in younger children, may lead to the emergence of drug-resistance. Reasons include: high viral load before treatment, poor and incomplete drug absorption because of the limited availability of paediatric formulations as well as changes in growth, and difficulties in adherence.

Drug resistance is of particular concern among children since they will need ART for longer periods of time than adults. Most children with HIV live in resource-poor settings.

Viral load monitoring helps determine the best first-line regimen and optimum times to switch; genotypic testing helps identify resistant mutations. Routine use of these options is not available in resource-poor settings where scant information on resistance rates associated with paediatric ART exists. With only two lines of ART in most resource-poor settings the need to preserve first-line regimens is critical.

The authors undertook a systematic search of online databases and conference abstracts including studies of acquired drug resistance after failure of first-line ART among children in resource-poor settings. By reviewing the current understanding of resistance rates and patterns of first-line paediatric regimens they sought “to gain insight into optimum switching strategies.”

From 1312 article and abstracts found, 15 peer-reviewed papers and 15 abstracts providing information on the emergence of drug-resistance to ART involving 3241 children in 15 countries (three in Latin America, three in Asia and nine in sub-Saharan Africa) were identified. Exclusion criteria included papers dealing with distinct issues such as comorbidity or adverse drug reactions or because original data was not reported.

Treatment failed in 1407 (40%) children.

15 studies reported virological failure and associated drug resistance in cohorts of children on ART followed for a median time of six to 50 months.

The other 15 studies were cross-sectional analyses of HIV drug resistance rates and patterns of treatment failure in 696 children with a median time on ART ranging from six to 62 months.

2303 (78%) children had an NNRTI-based regimen with either nevirapine or efavirenz. 19% (569) had PI-based regimens.

In all regions the NRTI backbones were stavudine, zidovudine and lamivudine and occasionally didanosine.

The proportion of children with at least one mutation ranged from 57% to 100%. In a subgroup analysis according to geographic region pooled proportions of drug resistance after failure of ART ranged from 75% (67-82) in Central and West Africa to 96% (91-100) in Asia.

The longer the time on ART, the greater was the risk for drug resistance.

Important differences in frequencies of reverse transcriptase and protease mutations were seen in Latin America compared to other regions. The authors suggest these can be explained by differences in the use of regimen.

In Latin America more thymidine analogue mutations were reported but less frequently the M184V mutation associated with lamivudine and emtricitabine; regimens in Latin America that combine NNRTIs, PIs and one or more NRTIs do not always contain lamivudine or emtricitabine.

Conversely in regions where lamivudine or emtricitabine were included in ART regimens M184V mutations were the first to be seen with thymidine analogue mutations delayed.

In southern Africa ritonavir-boosted lopinavir and full-dose ritonavir were the most commonly used PIs. The most frequent reported mutations from this region were V82A, I54V and M46I, all selected by lopinavir and ritonavir.

Limitations include rates of drug resistance associated with specific drug classes might be the result of something other than the drug regimen. The authors highlight the potential for transmitted or acquired resistance because of previous ART use for prophylactic or therapeutic purposes, a reality, they note of paediatric treatment programmes.

The selection of specific resistance mutations, they add, could not be linked to ART regimens used; the studies provide summary data on drug resistance mutations not individual data.

Resistant mutations were highest for nevirapine and efavirenz, suggesting use of first-generation and possibly second-generation NNRTIs is not feasible, the authors note.

Limited availability of licensed NRTIs in young children means that extensive NRTI resistance could make recycling of NRTIs in second-line ART difficult, if not impossible. 

The authors note further safety and efficacy data are needed to determine the usefulness of double-boosted PI regimens in children where NRTI backbone is no longer working.

Among PIs nelfinavir and single dose ritonavir were associated with an increased risk of resistance. Darunavir boosted with ritonavir and tipranavir are licensed for, and available in paediatric formulations offering promising alternatives to older PIs, note the authors.

With increasing access, limited drug regimens and the absence of effective monitoring or genotyping in resource-poor settings, resistance to at least two drug classes is likely to increase, they add.

The authors conclude “the future of an increasing number of children will depend on the availability of new generation ARVs and on pharmaceutical companies, donor agencies, and policymakers prioritising the development of second-line and salvage paediatric formulations.“

Sigaloff KCE et al. HIV-1 resistance-associated mutations after failure of first line antiretroviral treatment among children in resource-poor regions: a systematic review. Lancet Infect Dis 11:769-79, doi: 10.1010/S1473-3099(11)70141-4, 2011.