Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial

Abstract

Background Protease inhibitor (PI)-based therapy is recommended as first-line treatment for HIV-infected infants exposed to nevirapine prophylaxis. However, long-term use poses adherence challenges, is associated with metabolic toxicities, limits second-line options, and is costly. We report long-term outcomes of switching nevirapine-exposed children to nevirapine-based therapy after effective suppression of virus replication on a PI-based regimen. Methods At one site in Johannesburg, South Africa, 195 nevirapine-exposed children under 24 months of age who achieved virologic suppression <400 copies/ml while treated with a lopinavir/ritonavir (LPV/r)-based regimen were randomized to switch to nevirapine-based therapy (n=96) or remain on the LPV/r-based regimen (n=99). Children were followed a median of 156 weeks and 3 deaths occurred in each group. HIV RNA was quantified every 3 months. Findings By 156 weeks post-randomization, more children in the switch group (23.9%) than in the controls (11.1%) had viral failure (p=0.01) defined as confirmed viremia >1000 copies/ml. However, all (22/22) failures in the switch group were detected by 52 weeks compared with 50% in the controls. Children in the switch group (40.5%) were more likely to suppress to <50 copies/ml (primary endpoint of study) than controls (31.3%, p=0.01) and had better CD4 and growth responses initially after switching. Viral failure was related to non-adherence and pre-treatment drug resistance. In those without pre-treatment drug resistance, no significant difference in viral failure between the switch (14.0%) and control (9.5%) groups (p=0.34) was observed. Interpretation Viral load testing through 52 weeks can identify all children likely to fail this PI-switch strategy. Switching children once suppressed to a nevirapine-based regimen may be a valuable treatment option provided that adequate viral load monitoring can be done.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

“…The Nevirapine Resistance Study (NEVEREST), a randomized trial of switching NVP‐exposed infants from suppressive LPV/r‐ to NVP‐based ART (after at least 3 months of VL < 400 copies/ml), showed that this strategy can be successful in infants without evidence of transmitted NVP resistance on conventional testing 64, 197. Children switched to NVP had less long‐term dyslipidaemia and subcutaneous fat loss 112.…”

Non-AIDS Morbidity among HIV Patients

“…Special note: The randomized control trial supporting the use of this approach (148,161) defined virological suppression as a viral load ≤400 copies/mm 3 , with the goal of identifying the children who are more likely to be able to safely substitute LPV/r with NVP. The use of a higher viral load cut-off for determining virological suppression has not been studied in the context of this strategy.…”

“…A recent randomized clinical trial (148,161) and an ongoing randomized clinical trial (162) have evaluated a strategy in which LPV/r is started and later substituted with an NNRTI (NVP or EFV). Such PI-sparing strategies aim to reduce exposure to LPV/r, offer an easier approach to maintaining treatment and preserve PI-based therapy for second-line ART.…”

“…Such PI-sparing strategies aim to reduce exposure to LPV/r, offer an easier approach to maintaining treatment and preserve PI-based therapy for second-line ART. This approach has been shown to be safe and effective in the trial setting for children with sustained virological suppression achieved after receiving LPV/r-based first-line therapy, especially in the absence of HIV resistance to NNRTI before initiating ART (148,161). However, this approach may also add complexity to treatment programmes and may require access to virological monitoring.…”

Antiretroviral therapy for the management of HIV in children

“…Switching suppressed children from LPV/r to NVP for those <3 years or EFV for those >3 years resulted in sustained viral suppression in the Nevirapine Resistance Study (NEVEREST) studies. [20,21] Although switching to EFV in children >3 years and to NVP in those <3 years was successful in some instances, currently infants failing prevention of mother-to-child transmission (PMTCT) have prolonged NNRTI exposure for at least 6 weeks, rather than only a single dose as in NEVEREST, thus increasing the risk of subsequent significant NNRTI resistance. In NEVEREST-2, failure occurred more often in children with baseline NNRTI resistance (plasma RNA >1 000 copies/mL) when switched to NVP than in those remaining on LPV/r (22% v. 10%; p=0.009).…”