CROI: Therapeutic concentrations of efavirenz, Kaletra, could be difficult to achieve in some children, with or without rifampicin

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Therapeutic concentrations of some antiretrovirals could be difficult to achieve in some HIV-infected children in resource-limited settings according to a drug interaction study presented at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.

The study, by Dr Yuan Ren and colleagues, investigated two important drug interactions in children that have previously only been reported on in the adult population. They evaluated 58 children who were following a regimen of efavirenz (Sustiva) or Kaletra (lopinavir/ritonavir) with two nucleoside reverse transcriptase inhibitors (NRTIs) with and without rifampicin-based tuberculosis (TB) treatment.

The importance of rifampicin interactions

Tuberculosis is an extremely common infection in children with HIV in resource-limited settings, but rifampicin, a drug required for effective anti-TB treatment, has been shown to modestly reduce efavirenz concentrations in adults and dramatically reduce lopinavir concentrations (by more than 90%). To date however, there has been little information on whether dosage adjustments would be necessary when either of these antiretrovirals is given with rifampicin in children.

Efavirenz

In the first drug interaction study, following standard recommended dosing, the investigators looked at the concentrations of efavirenz when given for antiretroviral therapy (ART) alone (in 15 children) or co-administered with rifampicin (also in 15 children). Efavirenz concentrations were measured by validated Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods (KKGT; Netherlands). Three consecutive blood samples were taken 12 and 24 hours after intake. Since these children were not inpatients, efavirenz trough concentrations (Cmin) were estimated from the log-linear regression line of the three concentration-time points.

Glossary

drug interaction

A risky combination of drugs, when drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

treatment failure

Inability of a medical therapy to achieve the desired results. 

Efavirenz concentrations were not significantly different between those taking rifampicin and those who did not (p = 0.756). When 13 children returned after completing TB treatment for repeat sampling, the Cmin was not significantly increased.

Regardless of rifampicin administration, estimated Cmin in 50% of children was below the minimum recommended plasma concentration (<1 mg/l), raising concern about rapid emergence of efavirenz -resistance mutations and treatment failure.

Kaletra

Kaletra is lopinavir and ritonavir, in a 4:1 ratio coformulation. Ritonavir is added primarily for its ability to potently boost lopinavir concentrations in the body; and a previous study in adults had suggested that rifampicin’s negative effect on lopinavir concentrations could be overcome by the addition of more ritonavir (in a 1:1 ratio).

So the second interaction study tested whether this approach would work in children also taking rifampicin. Thus, lopinavir/ritonavir was given with two nucleoside reverse transcriptase inhibitors (NRTIs) to 15 children and the same drugs (but with lopinavir:ritonavir = 1:1) plus rifampicin given to 13 children. LC-MS/MS was used to determine lopinavir concentrations.

In all 28 children, lopinavir Cmin was above the minimum therapeutic level (1 mg/l) and lopinavir Cmin was similar between the two groups, confirming that additional ritonavir does slow lopinavir elimination and compensates for rifampicin’s lowering effect on lopinavir levels.

 

Pharmacokinetic MeasuresMedian (IQR) With Rifampicin(LPV:RTV = 1:1)
(n = 13)
Without Rifampicin(LPV:RTV = 4:1, Kaletra)
(n = 15)
p value
Tmax (h) 3.0 (2.0 to 4.07) 3.92 (2.78 to 4.0) 0.660
Cmax (mg/L) 11.9 (7.24 to 14.3) 14.2 (11.9 to 23.5) 0.038
Cmin (mg/L) 4.12 (2.89 to 7.66) 4.64 (2.32 to 10.4) 0.872
AUC0–12 84.29 (53.51 to 113.37) 113.70 (78.81 to 168.61) 0.056
Half life (h) 10.98 (5.44 to 16.61) 4.86 (3.82 to 8.29) 0.062

Conclusions

Although the study demonstrated that increasing the ratio of ritonavir to lopinavir would achieve adequate lopinavir levels, many in the audience were concerned about how this might increase toxicity — especially given the fact that ritonavir is one of the worst tolerated of all the antiretroviral drugs.

In addition, Dr Ren noted that large inter-patient variability was observed in lopinavir levels.

“Therapeutic drug monitoring should be considered for children receiving concomitant rifampicin,” said Dr Ren. She noted that the same would be true for patients on efavirenz, with or without rifampicin. “But again, this is approach is seldom available in developing countries where the need is greatest,” she concluded.

References

Ren Y et al. Plasma concentrations of efavirenz and lopinavir in children with and without rifampicin-based anti-TB treatment. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 77, 2007.