Younger, Smaller Children Show Less Success With ART
Although the ODYSSEY trial showed superior efficacy of dolutegravir (DTG)-based treatment than standard of care, data on predictors of treatment failure in children starting ART on DTG-based regimens are limited, wrote James Wyncoll, PhD, medical statistician at University College London, London, England, and colleagues in their abstract.
The researchers reviewed data on 381 children who started first-line ART: 189 with DTG and 192 with standard of care. Most of the children (82%) were in Africa, 13% were in Thailand, and 5% were in Europe. At baseline, the median age of the children was 10.5 years, and the median CD4 percentage was 20%. The median BMI-for-age z-score was -0.58, and 19% of the participants met the World Health Organization (WHO) criteria for stage III/IV disease.
The researchers considered the predictive values of baseline characteristics across four domains (anthropometrics, HIV indicators, hematology, and demographics) for treatment failure after 96 weeks.
Overall, 75 children experienced treatment failure by 96 weeks, including 24 in the DTG group and 51 in the standard-of-care group. Fewer children treated with DTG experienced treatment failure and the risk declined with increasing age, the researchers wrote. However, predictors of treatment failure were not significantly different between treatment groups, they said.
In the domain-specific models, after adjustment for weight and trial arm, independent and significant predictors of treatment failure included low BMI-for-age, low CD4%, WHO stage III/IV events, high neutrophils, and care at a location in Africa.
In a multivariate analysis, DTG treatment, lower weight, CD4%, ongoing WHO stage III/IV events, and African region remained as significant predictors of treatment failure ( P < .1). Neutrophils were no longer significant after adjustment for ongoing WHO stage III/IV events, and BMI-for-age was no longer a significant predictor after adjustment for CD4% and region.
'The findings of this study can help clinicians by identifying characteristics at ART initiation which predict a child's risk of treatment failure,' Wyncoll told Medscape Medical News . This study provides information on predictors of treatment failure in children starting ART for the first time, including those starting DTG regimens, he said.
Outside of clinical trials, adolescents receiving ART reportedly fared worse than younger children, but the current study showed that the risk for treatment failure declined with increasing age, Wyncoll said. 'We think it's likely that in trials, where participants have increased support, adolescents have good responses to treatment, and it is the youngest children who are at highest risk of treatment failure,' he noted. Reasons for greater treatment failure in younger children may include the need for different formulations, as well as the reliance on caregivers to administer the drugs, which can be difficult, he added.
Both CD4% and BMI-for-age are previously recognized predictors of treatment failure.
Takeaways and Next Steps
The study's findings support previous research showing young age as a strong risk factor for treatment failure with ART, Wyncoll told Medscape Medical News.
'Even with early diagnosis and ART, other studies like the EARTH cohort and the LIFE trial show high mortality in the first 2 years of life, especially within the first 6 months,' he said. 'The EARTH study found that an adverse maternal social environment was linked to poorer outcomes and higher treatment failure in young children, emphasizing the need for strong, sustained support for mothers during pregnancy and early life of infants, including emotional and adherence support,' he noted. Screening for and preventing opportunistic infections such as tuberculosis and giving nutritional support is essential to promote treatment success, and baseline CD4 percentage can help identify children at highest risk for treatment failure, he said.
The final model in the current study provides the basis for an online risk prediction tool for treatment failure, Wyncoll explained. Clinicians would enter a child's characteristics (such as treatment type, age, CD4%, and BMI for age) at ART initiation.
'Children are currently left behind when we consider novel treatment regimens,' Wyncoll said. 'Our work highlights the need for innovative approaches and more research into improved treatment for vulnerable children, such as different ART delivery methods or enhanced therapeutics,' he added.
Although the researchers concluded that predictors of treatment failure for children in the DTG and SOC groups were the same, the findings were limited by the low rates of treatment failure for the children on DTG, Wyncoll told Medscape Medical News . 'Further research is needed using real-world data from children starting dolutegravir to consolidate these findings,' he said.
Don't Discount DTG for Children
Relatively few studies have examined risk factors for virologic failure in children with HIV, especially those on DTG, said Monica Gandhi, MD, director of the University of California San Francisco (UCSF) Bay Area Center for AIDS Research and professor of medicine at UCSF, in an interview.
The current study findings showing a lower CD4 count when initiating ART or ongoing advanced HIV (as represented by the WHO stage III/IV events) or lower weight when starting ART were all risk factors for failure and were not unexpected, Gandhi told Medscape Medical News . 'What was surprising was to see DTG-based ART more associated with failure than standard-of-care (SoC) ART, since DTG is more potent and durable in adults,' she said.
The clinical takeaway is to try to start ART in children as soon as possible to avoid low CD4 counts or more advanced HIV on ART, both of which are risk factors for failure, Gandhi said. DTG-based ART should still be the standard of care among children, but additional research is need to determine into what kind of formulations work best younger ages, such as a dispersible tablet for oral suspension, she added.
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