Polly Clayden
Resistance in children and its association with virological failure was highlighted in two studies presented at the recent Retrovirus conference in Chicago. Another study from Lisa Frenkel's group revealed that, as we're seeing with adults, having the M184V/I (3TC) mutations, could also offer some benefit to children in salvage therapy.
Although there are still persistent question marks concerning the clinical use of both genotype and phenotype resistance testing, for adults these tests are now integrated into the standard of care in Europe and the US. [1, 2] They are also available for children in some countries. Dr Schmidt's group from Germany examined the incidence of resistance in their group of children, and took the unusual step of comparing the results to those obtained from an adult cohort [3].
Virological treatment failure appears to be more frequent in children than in adults, and the authors highlighted the following reasons - adherence to therapy seems to be more difficult, different pharmacokinetics may result in subtherapeutic drug levels, viral load is generally higher in children than in adults and the antiviral CTL response is less efficient in the first year of life. Since information on the prevalence of highly resistant viral strains may influence current guidelines for diagnostic and therapeutic management of children, their aim for this study was to evaluate drug resistant profiles in paediatric HIV infection.
Genotype and phenotype tests were performed on 46 samples from 35 children - age 2 months to 16.5 years (median 8.4 years), at the time of their first resistance test. Detailed drug histories were available for all the children. This revealed 15 (42.9%) of the samples to be resistant against one group of antiretrovirals, 13 (37.1%) against two and one sample (2.9%) against all three classes. 11 follow up samples were obtained from 9 children and in 7 cases resistance had increased. 5 samples including 2 follow ups showed nucleoside multi-drug resistance. Results were then compared adult samples to analyse the frequency of key mutations.
Nucleoside multi-drug resistance was found to be more frequent in children than adults in this study. They believed that this was explained by the past (and sometimes current) common practice of using dual nucleoside therapy for children, which is no longer the standard of care for adults. In addition this was also likely to be provoked by insufficient suppression of viral replication, which appears to be more frequent in children than in adults. The investigators found that NNRTI and PI resistance was lower in children than in adults, although they speculated that, 'A higher frequency, may only be a matter of time as suggested from the increase in resistance in most of the follow up samples'.
They explained that, although HIV infection may differ considerably between children and adults in its biology as well as treatment, and that this paediatric cohort may not reflect a standard population, however 'relevant information may be extracted from the comparison of paediatric and adult resistance profiles because reasons for resistance testing were identical for each group'. The investigators concluded that 'since resistance testing recently proved to be beneficial for the management of adult HIV infection, the prognostic relevance of geno and phenotypic resistance testing should be prospectively analysed for optimising therapy in HIV-1 infected children.' This study was aptly titled 'A call for resistance testing.'
Dr Susan Eshleman's group analysed resistance in children experiencing virological failure from the PACTG 377 [4]. In this study experienced children were randomised into one of four treatment arms using different combinations of d4T, 3TC, nevirapne, nelfinavir and ritonavir. Children were screened at baseline and at treatment failure.
Amongst their findings they reported that the selection of nevirapine mutations was far less common among children receiving 4-drug nevirapine containing combinations. They also found that although nelfinavir and ritonavir resistance was rarely detected at the time of failure, mutations asociated with these drugs as well as additional 3TC and nevirapine-associated mutations were frequently selected in children who maintained their initial study regimen after virological failure.
Finally to end on an optimistic note, Dr Lisa Frenkel and colleagues reported a beneficial effect for children in having the M184V/I mutation at baseline prior to starting salvage therapy in the PACTG 366 trial [5]. Children with and without the M184V/I mutations were evaluated for their response to a new regimen 4-drug combination. Regimens were dictated by their prior use of PIs and/or NNRTIs and included at least 2 agents that they had not used previously. Children having the M184V/I mutations had a greater chance of achieving undetectable viral load both at weeks 12 and 24. They concluded that 'the M184V/1 mutations may have a clinically beneficial effect in the suppression of viral load during salvage therapy.'
References
Clive Loveday...
How critical are resistance assays to routine management in children's care?
The arguments are the same as for adults, and personally I have no doubts that resistance testing is fundamental to effective patient management.
But do we have scientific evidence that resistance testing will support patient care?
In adults I know of about 8 or10 trials to evaluate resistance testing - Viradapt, GART, NARVAL etc, and one year ago I had no doubts. I was confident that trials would generate enough evidence to support their routine use.
Now I think that I probably underestimated the role played by drug levels and adherence (both of which can be particularly hard to achieve with kids).
So do we need another randomised, controlled trial?
Certainly with adults it would probably not be possible to set up another one, because the tests should now be more widely available anyway.
We've leapfrogged ahead, but as far as real, convincing evidence is concerned we're not really finding a massive difference between using and not using genotype testing - so far we haven't shown significance greater than 0.05.
To make the best use of resistance testing it is crucial that we include drug levels and adherence. A lot of people pay lip service to adherence, but I know that I for one can never successfully take medications for even a couple of weeks.
It is essential to realise that it is not possible to expect resistance testing to make a significant difference in isolation. It is only one of three critical factors, all of which need to be followed.
As far as kids are concerned, although, on one hand I think testing is vital for kids and when samples are sent down to me I do them, I must make a plea for randomised controlled trials. So I am keen to see PERA go ahead, we need at least one trial, we've got to get convincing evidence for children.
Have you heard any particular arguments against resistance testing for kids?
One reason why kids might not be getting resistance tests is because some would argue that, because kids have a more limited choice of drugs available to use, there's little choice after each failure. You could reverse it though and argue that there's all the more reason to give each treatment the best possible chance of working.
Are there significant differences from the point of view of evolution of resistance with kids?
From a virologist's point of view, the development of resistance is exactly the same in children as in adults. If you don't get enough drug concentrations - either because of PK or non-adherence - you will get the evolution of resistance - regardless of someone's age.
PENTA 5 produced some ambiguous results. Resistance was certainly slower to evolve, but kids have higher viral loads. The virus certainly can't be different but perhaps the way that the virus is handled is. The only explanation I can think of is the virus is being cleared more slowly - it can't be that replication isn't fast.
But kids get resistance just the same as anybody else; there's no doubt about that.
Stephane Blanche....
What is the situation with resistance testing for children in France? How many, for example have been done at your hospital?
Genotype is recommended for children exactly as it is for adults.
More than 100 tests have already been done at the Necker (Necker Hopital Enfants Malades), and analysis is underway, including a global comparison with adult data.
My feeling is that genotype is certainly more important for children, since virological failure rate is clearly higher than in adults. For PIs and NNRTIs the answer is nearly always the same. Resistance is nearly always found if these drugs have already been used. So it's not extremely useful.
However for nucleosides the pattern is extremely variable and probably useful for re-cycling old molecules.
Genotyping is also clearly recommended for newborn babies...
For newborns, genotyping is systematically done but in this case it is not so useful since all our infected babies are from mothers who were not treated during pregnancy.
As it is a very small number of cases I think it is reasonable to continue to test them anyway.
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