Doubling the dose of lopinavir/ritonavir (Kaletra) in children with HIV on rifampicin-based TB treatment fails to provide adequate lopinavir concentrations, according to a drug interaction study presented this week at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.
“It really leaves us with a gap between what is feasible, safe and effective treatment for this group of children who really need co-treatment [for HIV and TB] because of its huge benefit on survival,” said Dr Helen McIlleron, from the University of Cape Town, who presented the study findings.
Background
Antiretroviral therapy (ART) is recommended for infants with HIV because it dramatically reduces early mortality but the options for ART in children are fairly limited, especially in resource-limited settings. When young children also need treatment for active TB, options are even more restricted because rifampicin reduces the concentrations of nevirapine and the protease inhibitors such as Kaletra. Although the effect on efavirenz is less profound, an earlier study has reported that – even when given on its own – efavirenz fail to reach therapeutic levels in about half of children.. Furthermore, there are lingering concerns about the safety of efavirenz in young children.
Many clinicians have been trying to adjust the doses of lopinavir/ritonavir to provide an effective ART regimen for children with TB, using one of two approaches. One is to ‘super-boost’ lopinavir with extra ritonavir, increasing the ritonavir dose to equal that of lopinavir. The team from Cape Town has previously reported that this achieves acceptable lopinavir concentrations in 85% of children on rifampicin-based TB treatment.
“But it’s rather an impractical approach,” said Dr McIlleron. “It’s very difficult to implement as the dosing of the liquid formulations is complex, especially with the two different volumes that have been used for Kaletra and the extra ritonavir.”
A simpler approach would be just to double the dose of lopinavir/ritonavir (Kaletra), which has been shown to achieve acceptable concentrations in healthy adult volunteers. But it hasn’t yet been studied in children or patients.
The study
Seventeen children over six months of age with TB and HIV, and 24 control children without TB, were recruited before the study was eventually stopped by the Data Safety Monitoring Board. The median age was around 15 and 19 months, and weight 8.84 and 10.55 kg, in the children in the test and control groups respectively. Males were over-represented in the control group and they weighed significantly more.
Lopinavir/ritonavir was dosed according to body surface area: 460/115 mg/m2 for cases and 230/57.5 mg/m2 for controls.
Samples were collected immediately before dosing and at two, four and eight hours (and in a subgroup at twelve hours) after an observed treatment dose. Observing the dose was important because, “it tastes horrible. Children often tend to spit it out,” Dr McIlleron said.
Plasma lopinavir concentrations were then analysed using liquid chromatography/mass spectrometry.
Results
“We measured the steady-state concentrations of lopinavir in both groups and there were statistically significant and quite dramatic reductions in the lopinavir concentrations in the children with TB given double the usual dose of lopinavir/ritonavir,” said Dr McIlleron.
Lopinavir concentrations were highly variable in both groups, but the median trough concentration, Cmax and area-under-the-curve concentrations were reduced by 82%, 44% and 51% in the children receiving the double-dose lopinavir/ritonavir while on TB treatment. All these findings were statistically significant. There were three serious adverse events in children with TB, including some elevations in the enzyme ALT, which spontaneously resolved.
“This approach should not be recommended in young children,” Dr McIlleron concluded. “There is an urgent need to establish safe, effective and feasible co-treatment for young children with HIV associated TB.”
Another option she noted might be to swap rifabutin for rifampicin, which “is recommended in wealthier countries as being a better option to go with protease inhibitors. But rifabutin is not formulated for young children and it’s generally not available in high-burdened settings,” she said.
McIlleron H et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. Sixteenth Conference on Retrovirus and Opportunistic Infections, Montreal, abstract 98, 2009.