Just over one in ten (12%) children and adolescents living with HIV in Europe and Thailand take a break from antiretroviral treatment, usually as a result of their own decision, findings from the European Pregnancy and Paediatric HIV Cohort Collaboration, show.
In this pooled analysis from 19 cohorts from 17 countries, most children recovered well immunologically after restarting treatment. However, younger age and higher nadir (lowest point) CD4 percentage during the treatment interruption predicted better immunological recovery.
While lifelong antiretroviral treatment (ART) is recommended for all with HIV infection, pill burden, side-effects and interference with everyday life affects long-term adherence, especially among adolescents. Randomised controlled trials on the safety of planned treatment interruptions in adults have found a higher incidence of infections and death rates restarting treatment. Adult treatment guidelines do not recommend treatment interruption.
Findings from the only two randomised trials (PENTA 11 and CHER) evaluating the consequences of planned treatment interruptions in children suggest treatment interruptions may be more suitable for children than adults. The immunological course of HIV infection in children differs from that in adults. In the first years of life, children experience moderate immune suppression but after starting antiretroviral treatment their immune response is stronger than in adults.
In children with HIV under five years of age, the CD4 percentage rather than CD4 count is used to evaluate HIV progression and response to ART. The CD4 percentage is the percentage of white blood cells that are CD4 cells.
Unplanned treatment interruptions continue to occur, often in children and young people who have irregular attendance, recent side-effects or treatment failure. This may mean poorer virological and immunological status at the time of treatment interruption compared to participants in experimental trials.
A French study of 483 children found that after one year on ART, 7% had a treatment interruption of three months or longer, with 30% having a treatment interruption after five years on ART. Four years after treatment interruption 53% of children back on ART for six months or longer had a CD4 percentage greater than 25, compared to 74% in a matched control group on continuous ART.
A study in the US of 72 children with an unplanned treatment interruption found that those with the greatest gains in CD4 percentage while on treatment had the greatest declines off treatment. CD4 recovery after restarting treatment was not investigated.
The identification of children and adolescents at risk of poor recovery is important for the timely restart of treatment. The researchers therefore aimed to investigate factors that might predict improved immunological recovery after restarting treatment. They hypothesised that these may include age and nadir CD4%.
Data from paediatric HIV-positive cohorts were pooled. Children under 18 years of age on ART for more than six months before a treatment interruption of 30 or more days were included. CD4 percentage at the restart of ART and in the long-term (up to 24 months after restarting ART) after the first treatment interruption was modelled.
From a total of 7358 children on ART, 779 with at least one treatment interruption were included in the analysis.
The median age at first treatment interruption was 10.1 years (IQR: 6.4-13.6) after being on ART for 5.5 years. The median treatment interruption was 9.0 months (IQR: 3.5-22.5).
The primary reason for treatment interruption was the patient’s decision and/or non-compliance (49%), followed by treatment failure (22%), doctor’s decision (17%) and side-effects (9%).
A third had more than one treatment interruption. The second, third and fourth treatment interruptions happened at 13.8, 14.8 and 15.8 years of age, respectively.
The children had a relatively good immunological status at the first treatment interruption with a mean CD4 percentage of 27.3% (standard deviation 11%). However, only 27% had a suppressed viral load (< 400 copies/mL).
At the end of treatment interruption the mean CD4 percentage was 19.2% (95% CI: 18.3-20.1%). Two years after restarting ART, it rose to 27.1% (95% CI: 26.2-27.9%), therefore reaching the pre-treatment interruption value, with half the increase in the first six months.
This may support findings from the CHER and PENTA 11 trials suggesting that treatment interruption may be a safe choice with regular CD4 monitoring, even if not routinely recommendable. However, multivariable analysis from this real-world setting shows several factors affecting recovery after treatment interruption.
Children under three years of age at the first treatment interruption had the highest CD percentage at restart of treatment and in the long-term (up to 24 months). After adjusting for CD4 percentage during treatment interruption, CD4 percentage recovery was highest in the youngest children, suggesting that older children have a decreased ability to reconstitute CD4 cells.
Long-term CD4 percentage recovery after restarting ART was highest among those with a treatment interruption of less than three months, those who restarted ART after the year 2000 and those with a CD4 percentage nadir of 25% or more (all, p < 0.001).
In general, a lower CD4 percentage during the treatment interruption was associated with poorer immunological recovery after restarting and in the long term. Nonetheless, children with a CD4 percentage nadir < 15% during treatment interruption whose viral load had previously been suppressed reached a better long term CD4 percentage than those with a detectable viral load. Viral load had no effect on recovery in children with CD4 percentage nadir ≥ 25%.
The authors caution that while young children show potential for good recovery, CD4 monitoring during treatment interruption is critical so that treatment is restarted before there are any significant decreases in CD4 cell count.
Objectives: The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART).
Methods: Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for > 6 months before TI of ≥ 30 days while aged < 18 years were included. CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression.
Results: In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged < 3 years at the start of TI. Long-term CD4% was highest in those with a TI lasting 1 to <3 months, those with r-ART after year 2000 and those with a CD4% nadir ≥ 25% (all P < 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir < 15% during TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir ≥ 25%.
Conclusions: After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI.
The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group