Efavirenz-based treatment is a safe and effective treatment option for children living with HIV previously exposed to nevirapine for the prevention of mother-to-child transmission (PMTCT) who achieved viral suppression with a regimen based on ritonavir/lopinavir, according to a study published in the Journal of the American Medical Association.
“Switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound…or viral failure…in this cohort of nevirapine-exposed children initially virally-suppressed on ritonavir-boosted lopinavir,” comment the investigators.
In resource-limited settings, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine has been widely used by HIV-positive mothers and their infants for PMTCT. Nevirapine has a low barrier to resistance, and resistance to nevirapine also confers resistance to efavirenz, another drug in the NNRTI class. For this reason, it is recommended that infants with HIV exposed to nevirapine should receive an antiretroviral regimen based on the protease inhibitor ritonavir/lopinavir.
But paediatric treatment with efavirenz-based therapy is attractive for a number of reasons. Possible advantages include once-daily dosing, harmonisation of treatment with that recommended for older children and adults, simplification of treatment for tuberculosis and the preservation of ritonavir/lopinavir for second-line therapy.
With these potential advantages in mind, an international team of investigators designed a study to see if nevirapine-exposed children, who achieved sustained viral suppression (viral load below 50 copies/ml) using a combination based on ritonavir/lopinavir, could switch to efavirenz-based therapy without risking viral failure.
The study was randomised and open-label. The population comprised 298 children aged under 36 months who received care at a single treatment centre in Johannesburg between 2010 and 2013. All had been exposed to nevirapine for PMTCT and had been taking ritonavir/lopinavir-based ART for an average of 3.5 years. The average age was 4.3 years. All had fully suppressed viral load.
Follow-up was for 48 weeks. The study was designed to determine the non-inferiority of efavirenz-based treatment in terms of viral rebound (one or more increase in viral load to above 50 copies/ml) and viral failure (sustained increase in viral load to above 1000 copies/ml). Secondary endpoints included changes in CD4 cell count and percentage, safety and side-effects.
A total of 150 children switched to efavirenz, the remaining 148 children remained on ritonavir/lopinavir. Study retention was excellent, with 98% completing 48 weeks of follow-up.
The probability of viral rebound was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir/lopinavir group. Probabilities of viral failure were 0.027 (n = 4) for the children treated with efavirenz and 0.020 (n = 3) for those taking ritonavir/lopinavir. Efavirenz-based treatment was therefore shown to be non-inferior to therapy based on ritonavir/lopinavir.
Two of the four children experiencing viral failure with efavirenz switched back to ritonavir/lopinavir and re-established viral control. Both had NNRTI-associated resistance mutations. Loss of viral control in one child treated with efavirenz was due to treatment interruption caused by a disturbance in liver function. After this was resolved, therapy with efavirenz was re-initiated and viral control re-established. No resistance was detected. The fourth child had viral failure associated with severe household disruption.
Children in the efavirenz group had better lipid profiles than those taking ritonavir/lopinavir. Both groups maintained CD4 cell counts and percentages within the normal range; percentages were modestly higher for those treated with efavirenz (2.88 units). Elevations in ALT were more common in the efavirenz group, but all instances were mild and there were no cases of rash.
Approximately a quarter of children taking efavirenz reported unusual dreams or nightmares at week four, but by week eight these had largely resolved. Two children in the efavirenz group experienced seizures; both were associated with a genetic mutation that can lead to high blood concentrations of efavirenz.
Adherence rates were similar in both groups.
“This study provides evidence to support the safety and efficacy of switching to efavirenz, the recommended drug for children older than 3 years, among virally suppressed children,” write the authors. “Switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure.”
Coovadia A et al. Efavirenz-based antiretroviral therapy among nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial. JAMA 314: 1808-17, 2015.