Virological response and resistance among HIV-infected children receiving long-term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: Observational analyses within the randomised ARROW trial

Abstract

Background: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring.

Methods and findings: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI -3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post-week 24 was spent with persistent low-level viraemia (80-5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years' rebound. Nineteen out of 48 (40%) VLs 1,000-5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes.

Conclusions: In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring.

Trial registration: ISRCTN Registry, ISRCTN24791884.

Fig 1. Flow diagram of children included in virological analyses.

* Results presented in main text. ** Results presented in S1 Appendix. † 97% of children enrolled after 29 May 2008. Abbreviations: ART, antiretroviral therapy; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; VL, viral load.

Fig 2. VL suppression in 2NRTI+NNRTI maintenance regimen after median 4 years on ART.

Note: 95% CI for risk differences were <80 copies/ml [−4.4% to +8.0%], <200 copies/ml [−4.5% to +7.5%], <400 copies/ml [−3.6% to +8.2%], <1,000 copies/ml [−3.4% to +8.0%], <5,000 copies/ml [−1.1% to +8.7%], and <10,000 copies/ml [−0.8% to +8.4%]. Abbreviations: ART, antiretroviral therapy; CDM, clinically driven monitoring; LCM, laboratory plus clinical monitoring; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; VL, viral load.

Fig 3. Predicted NRTI and NNRTI susceptibility in 2NRTI+NNRTI with VL >1,000 copies/ml after median 4 years on ART (n = 110).

Note: risk differences and 95% CI between CD4 monitoring versus no CD4 monitoring with intermediate/high-level resistance were 3TC 1.0% [−13.4% to +15.4%], ABC 1.4% [−15.5% to +18.2%], ZDV 5.0% [−5.9% to +15.9%], DDI 1.1% [−16.1% to +18.3%], D4T 8.0% [−6.3% to +22.3%], FTC 1.0% [−13.4% to +15.4%], TDF 7.7% [−5.9% to +21.4%], NVP 4.7% [−14.6% to +5.2%], EFV 1.3% [−12.2% to +9.5%], ETR 0.0% [−18.1% to +18.2%], and RPV 11.6% [−28.6% to +5.5%]. Abbreviations: ART, antiretroviral therapy; CDM, clinically driven monitoring; LCM, laboratory plus clinical monitoring; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; VL, viral load.

Fig 4. VL response in 204 children randomised to 2NRTI+NNRTI initially responding to ART.

(a) VL classification by week on ART. (b) Mean VL during pLLVL and rebound. Note: (a) carrying forwards current state where VL was missing; carrying backwards, “VL response”, where week 4 VL was missing (n = 16). Abbreviations: ART, antiretroviral therapy; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; pLLVL, persistent low-level viral load; VL, viral load.

Fig 5. (a) Predicted drug susceptibility at rebound and (b) change in susceptibility over a median 2 years in those randomised to 2NRTI+NNRTI maintenance (n = 12).

Abbreviations: 3TC, lamivudine; ABC, abacavir; D4T, stavudine; DDI, didanosine; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine.