HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Abstract

Background: The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold.

Methods: PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end.

Results: Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later.

Conclusions: Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

Figure 1

Kaplan-Meier curves displaying the time from reaching the 1000 criteria to switch in the low-threshold arm (solid-line), time from the 1000 criteria to the 30000 criteria in the higher-threshold arm (dotted-dashed-line), and time from the 1000 criteria to switch in the higher-threshold arm (solid-dashed-line) by first-line NNRTI-based or PI-based antiretroviral therapy (ART). The 1000 criteria were defined as not achieving HIV-1 RNA <1000c/ml by week 24, confirmed rebound ≥1000c/ml thereafter or CDC stage C event. The 30000 criteria were defined as not achieving HIV-1 RNA <30000c/ml by week 24, confirmed rebound ≥30000c/ml thereafter or CDC stage C event. Children in the low-threshold arm were randomized to switch at the 1000 criteria, and those in the higher-threshold arm to switch at the 30000 criteria. Ninety-four children reached the 1000 criteria during the trial, but 93 children are displayed in the figure as 1 child on PI-based first-line ART randomized to switch at the low-threshold ended follow-up on the same day as reaching the 1000 criteria. PI=protease inhibitor, NNRTI=non-nucleoside reverse transcriptase inhibitor

Figure 2

Major IAS resistance mutations accumulated on first-line antiretroviral therapy (ART). Children are displayed in 4 groups defined by the class of ART initiated as first-line (PI-based versus NNRTI-based) and their randomized switch threshold (low=1000c/ml versus higher=30000c/ml). Resistance tests were required on first-line in both randomized switch threshold arms, while children were on ART, at 1) the last sample with RNA ≥1000c/ml before switch, 2) the last sample after confirmed RNA ≥1000c/ml (e.g. if not switched because ‘30000 criteria' not met and RNA re-suppressed to <1000c/ml), and 3) samples with RNA ≥1000c/ml at 4 years or trial end. IAS=International AIDS Society-USA, PI=protease inhibitor, NNRTI=non-nucleoside reverse transcriptase inhibitor, NRTI=nucleoside reverse transcriptase inhibitor, 3TC=lamivudine, d4T=stavudine, ZDV=zidovudine, ABC=abacavir, ddI=didanosine, LPV/r=lopinavir/ritonavir, NFV=nelfinavir, RTV=high-dose ritonavir, EFV=efavirenz, NVP=nevirapine,

Figure 3

Second-line antiretroviral therapy (ART) options. Children are displayed in 4 groups defined by the class of ART initiated as first-line (PI-based versus NNRTI-based) and their randomized switch threshold (low=1000c/ml versus higher=30000c/ml). The clinician chosen initial first-line ART is displayed along with current WHO recommended second-line and the susceptibility to this potential second-line regimen by the Stanford algorithm. The proportion of children susceptible to the potential second-line options assumed that children not meeting requirements for resistance testing were susceptible and excludes children with unavailable resistance results. Second-line containing EFV is only recommended for children >3 years and has been noted on the figure. PI=protease inhibitor, NNRTI=non-nucleoside reverse transcriptase inhibitor, NRTI=nucleoside reverse transcriptase inhibitor, 3TC=lamivudine, FTC=emtricitabine, d4T=stavudine, ZDV=zidovudine, ABC=abacavir, ddI=didanosine, TDF=tenofovir, LPV/r=lopinavir/ritonavir, FOS/r=fosamprenavir/ritonavir, RTV=high-dose ritonavir, NFV=nelfinavir, NVP=nevirapine, EFV=efavirenz