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Virologic failure detected in a quarter of ART-treated children in Tanzania
Michael Carter, 2016-12-28 10:20:00
A quarter of
children and adolescents in Tanzania taking antiretroviral therapy (ART) have major
resistance to one or more anti-HIV drug, investigators report in AIDS.
In 86% of patients, resistance was
acquired during therapy and significant risk factors for acquired resistance
included therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI).
Use of World Health Organization (WHO) criteria for immunological failure of treatment – which triggers a
change in therapy – would have detected only 4% of cases of virological
“To our knowledge,
this is one of the first studies to comprehensively assess virologic failure
and the acquisition of HIV-DRM [drug resistance-associated mutations] among a
large paediatric population in Sub-Saharan Africa,” comment the investigators.
“Key findings are a high rate of both virologic failure and acquired HIV-DRM
after a median of over 4 years of ART and an increased risk of both virologic
failure and HIV-DRM among participants receiving NNRTI, those with younger age
at ART initiation and female patients.”
In 2015, an
estimated 1.8 million children were living with HIV worldwide, the vast majority
in sub-Saharan Africa. Only 49% of children in need of ART are receiving this
There are limited
data on the long-term virologic effectiveness of ART in children and
adolescents in resource-limited settings, where access to viral load monitoring
is limited. An international team of investigators therefore designed a
prospective cohort study involving 213 ART-treated children and adolescents who
received care in rural Uganda. Their aims were to determine the prevalence of
virologic failure (a viral load above 1000 copies/ml after 12 months of
treatment), the prevalence of major resistance-associated mutations and the
risk factors for virologic failure.
participants had been receiving ART for a minimum of one year (median, 4.3
years) and were aged under 18 years (median, 11 years). The majority (55%) had
symptomatic HIV disease (WHO stages 3 and 4. The most commonly used first-line
regimen was zidovudine/lamivudine/NNRTI (55%). At the time of analysis, 85% of
participants were taking NNRT-based therapy. Good adherence (no missed doses in the
previous four weeks) was recorded in 85% of individuals, but a quarter had changed
their regimen at some point because of drug shortages or stock-outs.
At the time of
analysis, 25% of participants had a viral load of 1000 copies/ml or above, thus
meeting the WHO definition for virologic failure. Median viral load in these
people was 20,615 copies/ml. An additional 18% of individuals had a detectable
viral load of less than 1000 copies/ml.
percentage rose from 12% at ART initiation to 26% after 12 months of
therapy, reaching a maximum of 31% after 60-65 months on ART. Immune recovery
tended to be weaker among individuals with virologic failure, reaching 22% after 12 months compared to 27% for those without virologic failure.
virologic failure were NNRTI-based ART (aOR = 7.32; 95% CI, 1.51-35.46, p =
0.013), sub-optimal adherence (aOR = 3.90; 95% CI, 1.11-13.68, p = 0.034) and
female sex (aOR = 2.57; 95% CI, 1.03-6.45, p = 0.04). A higher CD4 percentage
and older age were both protective against virologic failure.
Of the participants
with virologic failure, 90% had at least one major resistance mutation;
resistance to an NRTI was found in 81% of these individuals, with 90% having
resistance to an NNRTI.
pre-ART blood samples from 44 people with a major mutation showed that 85%
had acquired a key resistance mutation during therapy, the remaining 15% having
Risk factors for
acquired resistance were NNRTI-based therapy (aOR = 10.73; 95% CI, 1.75-65.70,
p = 0.01) and female sex (aOR = 3.99; 95% CI, 1.40-11.41, p = 0.01). There was
a non-significant association between poor adherence and acquired resistance.
Higher CD4 percentage and older age were protective against this outcome.
criteria for immunological treatment failure in children are a CD4 count below
200 cells/mm3 or 10% in the under-5s, and a CD4 count below 100
cells/mm3 for children aged 5-15 years. Only 3.7% of major resistance
identified in the present study would have been picked up using WHO
immunological failure criteria.
“Our study found
high rates of virologic failure and emerging HIV-DRM in this paediatric
population on long-term ART in rural Tanzania,” conclude the authors. “These
results reinforce the current knowledge about the low sensitivity of the WHO
criteria for immunological treatment failure in children and adolescents. These
findings…raise concern about the effectiveness of current paediatric ART
programmes in Sub-Saharan Africa, calling for a critical review of current guidance.”