Risk factors for treatment failure in children: ritonavir and advanced disease strong predictors

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Ritonavir used alone as a third drug is a strong predictor of virologic failure in children receiving antiretroviral treatment, according to an analysis of data from the International Epidemiological Databases to Evaluate AIDS (leDEA) Southern Africa's paediatric antiretroviral cohorts, presented by Mary Ann Davies et al. at the Fifth IAS Conference on Pathogenesis, Treatment and Prevention, in Cape Town.

Advanced immunosuppression was also a predictor of treatment failure.

Fifty percent of children with virologic failure were not switched to second-line antiretroviral therapy (ART) and, for those who did receive second-line treatment, a delay of close to five months between failure and switching occurred.

Glossary

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

treatment failure

Inability of a medical therapy to achieve the desired results. 

hazard ratio

Comparing one group with another, expresses differences in the risk of something happening. A hazard ratio above 1 means the risk is higher in the group of interest; a hazard ratio below 1 means the risk is lower. Similar to ‘relative risk’.

inter-quartile range

The spread of values, from the smallest to the largest. The inter-quartile range (IQR) only includes the middle 50% of values and measures the degree of spread of the most common values.

retention in care

A patient’s regular and ongoing engagement with medical care at a health care facility. 

As more children access antiretroviral treatment, a corresponding increase in the number of treatment failures will occur, requiring second-line treatment.

The absence of a definition of virologic failure in children, coupled with the lack of studies in resource-limited settings about treatment failure and outcomes of second-line treatment, severely handicap the effective management of HIV in children.

The World Health Organization does not recommend the use of routine viral load monitoring regarding decision-making on treatment failure. Viral load monitoring is suggested when CD4 counts and clinical criteria are conflicting. WHO suggests a viral load greater than 10,000 copies as indicative of treatment failure in adults. Thresholds for children have – as yet – not been defined.

However, levels of HIV RNA that are greater than 100,000 copies in children are associated with a higher mortality rate and suggest treatment should be switched.

To understand the probabilities of virologic failure in addition to the outcomes of second-line therapy, an analysis was undertaken of children under sixteen years of age who started combination therapy at leDEA Southern Africa sites and who received routine six-monthly virologic monitoring.

Failure was defined as two consecutive viral loads above 10,000 copies/ml more than five months after the start of antiretroviral treatment.

Among 5484 children, median follow-up was 16 months (IQR 6 to 29). 310 children had virologic failure and 146 were switched to second-line treatment; at three years cumulative probabilities were 11.4% (95% CI: 10.1 to 12.8) and 6.0% (95%CI: 5.0 to 7.2) respectively. The median time between failure and switch was 4.8 months (IQR 1.5 to 9.4).

Characteristics of children at the start of antiretroviral therapy and the corresponding association with virologic failure (where significant) included:

  • being under 12 months of age (21%)
  • having a viral load in excess of one million copies/ml (21%)
  • being severely immunosuppressed, as defined by WHO (82% – adjusted hazard ratio 2.01 [1.20 to 3.36])
  • being at WHO stage 3 or 4 (75%)
  • ritonavir being used alone as a third drug (versus lopinavir/ritonavir or a non-nucleoside reverse transcriptase inhibitor) (7% – adjusted hazard ratio 2.69 [1.72 to 4.20]).

Survival and retention in care of children one year after switching to second-line therapy were 97.1% (95%CI: 91.9 to 99.1) and 88.7% (95% CI: 81.7 to 93.5) respectively. Fifty-five per cent had viral load suppression one year after switching to second-line therapy.

The authors noted that findings from this population may not be applicable to all South African cohorts, since the centres and clinics involved in the study are well-resourced. No good information was available on adherence or co-infection.

Ritonavir liquid, less frequently used in developed world settings, was in use due to the limited range of antiretroviral formulations suitable for young children. The study authors said that they were unable to determine whether the unpleasant taste of ritonovir liquid affected adherence and thus led to higher rates of virologic failure seen in ritonavir-treated children.

Fifty percent of children who had failed first-line treatment were not switched to second-line treatment, and the fifty percent who were switched experienced a considerable delay between the diagnosis of treatment failure and switching to second-line therapy.

Further information

A powerpoint presentation by Mary-Ann Davies and a webcast of the conference session in which it was presented are available on the IAS 2009 website.