With expanding access to antiretroviral therapy (ART) for HIV-infected children, increasing numbers are likely to experience treatment failure and require second-line regimens. Before 2010, WHO pediatric guidelines did not define virologic failure (VF) and viral load monitoring remains unavailable in most resource-limited settings.1,2 In contrast, industrialized country guidelines stipulate strict viral load criteria for switching at thresholds as low as 2 consecutive measurements >400 copies per milliliter.3,4
Due to poor access to viral load monitoring in resource-limited settings, there is limited published data on VF in children.1 Existing studies are limited by cohort size, exclusive use of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and/or failure definitions based on a single elevated viral load measurement.5-9 Poor access to and lack of experience with second-line therapy, and national policies that may restrict second-line use, have resulted in low numbers and proportions of children being switched even in larger cohorts.5,6,10-14 Predictors of which children are switched in resource-limited settings have therefore not been examined.
The International epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa collaboration includes 7 South African pediatric ART programs with data on more than 6000 children who had initiated treatment before 2008.15,16 Regular viral load monitoring (at least 6-monthly) is part of routine ART care in South Africa.17 However, until 2010, national pediatric treatment guidelines did not provide clear direction on management of VF.17 We aimed to examine the probability of VF and its associations, and, in children with VF, to determine the probability of switching to second-line and identify factors that predicted which children were switched.
Study Design, Setting and Population
Data for this multicenter analysis were collected prospectively at sites. Each site has institutional ethical approval for contribution of data to IeDEA analyses and transferred data anonymously to the IeDEA data center between May 2007 and February 2008. The analysis included treatment-naive children (<16 years) initiating ART with ≥3 antiretroviral drugs between June 1999 and February 2008.
All treatment sites are part of the South African national treatment program that commenced in April 2004 with the following first-line regimen guidelines: stavudine (d4T), lamivudine (3TC), and either efavirenz (EFV) or if <3 years/<10kg, a protease inhibitor (PI).17 For most children, this was lopinavir/ritonavir (LPV/r), however, ritonavir alone (RTV) was recommended for children with tuberculosis or <6 months old.17 The latter 2 recommendations changed during 2007; LPV/r with additional RTV boosting was introduced for children with tuberculosis, and LPV/r dosing recommendations became available for children <6 months old.18,19 Some cohorts introduced these practices before 2007, and also used more varied regimens before commencement of the national program, including NNRTI-based regimens in children <3 years old, RTV alone as the “third drug” in children of all ages, and zidovudine (ZDV) instead of d4T. National guidelines were otherwise adhered to in all provinces and permitted restricted individual drug substitution for intolerance or nonavailability of the recommended drug in suitable formulation.17
National guidelines second-line regimens were ZDV + didanosine with either LPV/r (EFV-based first line), or an NNRTI (PI-based first line).17 The NNRTI was nevirapine (NVP) for children <3 years old at switch, and EFV for older children.17
Decisions to switch could be made by the program clinician without formal Department of Health approval. Second-line regimens were accessible at all sites.
National guidelines advised single dose NVP (sdNVP) for mother and infant for prevention of mother to child transmission (PMTCT), with triple ART for pregnant women with WHO stage 4 disease or CD4 ≤200 cells per microliter.20,21 However, in the Western Cape province, PMTCT programs began before national roll-out, with a variety of regimens being used including sdNVP or ZDV from 34 weeks ± sdNVP. Similarly, after national implementation of the sdNVP regimen, the Western Cape province and McCord Hospital used more effective PMTCT regimens (Table 1).22
Sociodemographic and clinical data at ART start included age, gender, clinical stage [stage 3 (2002 3-stage WHO classification) and stages 3/4 (2005 4-stage WHO classification) were combined],23,24 exposure to PMTCT regimens and starting regimen. Weight, viral load, CD4 absolute count and percent were available at ART start and 6-monthly thereafter. Access to viral load and CD4 measurement was similar across sites. Viral load measurements were performed using Amplicor 1.5 (Roche Diagnostics, Basel, Switzerland) or NucliSens EasyQ assays (bioMerieux, Durham, NC), which have good comparability.25 Severe immune suppression was defined according to WHO guidelines.2 “Baseline” measurements were those taken closest to ART initiation and within 6 months (CD4 and viral load) or 2 weeks (weight) prior, to 1 week after commencing ART. Sex-adjusted weight-for-age z scores (WAZ) were calculated using WHO 2007 reference values for children ≤10 years of age.26
VF was defined as 2 consecutive (≤12 months apart) viral load measurements ≥400 copies per milliliter with the second being >1000 copies per milliliter, and both taken after 24 weeks on ART, and not during a treatment interruption. Sensitivity analyses used different thresholds (400, 5000 and 10,000 copies/mL) to define VF. Children were considered to have switched to second-line if any of the following occurred <1 year after a viral load measurement >400 copies per milliliter: (1) commencement of ≥2 new drugs including a class switch from PI to NNRTI or vice versa; (2) class switch from NNRTI to PI or vice versa only, with reason documented as treatment failure; or (3) change of both NRTIs and change from RTV to LPV/r with reason documented as treatment failure. Immunologic failure was defined according to South African guidelines criteria for switching as either CD4% below baseline value after 24 weeks of therapy or CD4% <50% of peak value during preceding treatment.
Continuous and categorical variables were summarized using medians and interquartile ranges (IQR) and proportions, respectively. Kaplan-Meier probabilities of virologic and immunologic failure and switch were estimated. Predictors of failure and switch were determined using Cox-proportional hazards models stratified by site to account for between-site heterogeneity. Only children with ≥6 months of follow-up after failure were included in the switch model. The following variables were included a priori in multivariable models: age, gender, and immune suppression at ART initiation (failure model); age, gender and treatment duration at time of failure (switch model). Thereafter, multivariable models retained variables with adjusted P values <0.1. In comparison to known lack of PMTCT exposure, missing PMTCT exposure information had no effect on failure, so these categories were combined. Separate failure models were generated including and excluding WAZ and stage, as missing data for these variables and exclusion of children >10 years old due to lack of WHO WAZ reference values substantially reduced the number of children that could be included in the model. The proportional hazards assumption was met for all models. Statistical analyses were performed using Stata version 10 (STATA Corporation, College Station, TX).
Data from all South African IeDEA sites providing pediatric ART were included (Table 1). This comprised 6266 children of whom 781 (12%) were excluded for the following reasons: missing or inconsistent baseline data (n = 85), non-naïve (n = 39), mono/dual therapy (n = 64) and starting regimen not recorded (n = 593). The final dataset comprised 5485 children (49% female) with median (IQR) follow-up of 16 (6-29) months. During follow-up, 344 (6%) children died, 411 (7%) were lost to follow-up and 885 (16%) were transferred out after median durations of 1.5, 5.8, and 12.9 months, respectively. There were 13,877 viral load and 12,749 CD4 percent measurements during follow-up with median (IQR) intervals between measurements of 168 (104-190) and 168 (126-197) days, respectively.
Most children were severely ill at ART start (Table 2). The median (IQR) age of children commencing ART was 42 (15-82) months. The NRTI backbone was d4T/3TC for 89% of children. The most common “third” drugs were EFV (55%), LPV/r (33%), RTV alone (7%), and NVP (5%).
The estimated probability of failure (second elevated value ≥ 1,000 copies/mL) by 36 months was 19.3% [95% confidence interval (CI): 17.6 to 21.1, Fig. 1]. Of the 523 children with VF, 311 (59%) had never been virologically suppressed. Among these children whose viral load was never <400 copies per milliliter, 217 had both baseline and ≥1 subsequent viral load measurement performed between 6 and 15 months on ART, and 121 (55%) showed a virologic response to therapy (≥1 log10 reduction from baseline viral load during the first year on ART). Using different thresholds for the second unsuppressed viral load, the 36-month estimated probability of failure ranged from 14.6% (95% CI: 13.1 to 16.3) (cut-off = 10,000 copies/mL) to 21.1% (95% CI: 19.3 to 23.0) (cut-off = 400 copies/mL) (Fig. 1). By 1 year and 3 years on ART, the estimated probabilities of a single viral load measurement >1,000 copies per milliliter were 16.9% (95% CI: 15.8 to 18.1) and 32.1% (95% CI: 30.2 to 34.1), respectively. By 3 years, 384 children had immunologic failure with an estimated cumulative probability of 12.6% (95% CI: 11.3 to 13.0). The probability of immunologic failure was lower than that for all definitions of VF, except in the early months as the immunologic failure definition did not require confirmation.
In the multivariable model of associations with VF, viral load >1 million copies per milliliter at ART initiation was the only disease characteristic that predicted failure (Table 3). After adjustment for gender, age, baseline viral load, and immune suppression, failure risk was increased with use of either NVP [adjusted hazard ratio (aHR): 1.77; 95%CI: 1.11 to 2.83] or RTV alone (aHR: 2.39; 95% CI: 1.57 to 3.64) compared with EFV in the initial regimen. Known PMTCT exposure was also associated with failure (aHR: 1.40; 95% CI: 1.02 to 1.92). Results were very similar using different thresholds to define VF. Results were also similar if additionally adjusted for WHO stage and WAZ, neither of which remained independently associated with failure. A further model was developed excluding children with virologic non-response, and results were similar except for an attenuated effect of PMTCT. Results of all additional analyses are shown in (see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A146).
Switching to Second-Line
The estimated probability of switching to second-line by 3 years after ART initiation for all children was 6.2% (95% CI: 5.2 to 7.5, Fig. 1). Of the 153 children switched, 8 did not meet the VF criteria because there was only 1 unsuppressed viral load measurement (n = 7), or consecutive measurements were both before 24 weeks on ART (n = 1). Of 252 children with ≥1 year of follow-up after failure, 38% (95% CI: 32% to 45%) were switched. The median (IQR) time to switch from failure was 5.7 (2.9-11.0) months and from first unsuppressed viral load was 9.5 (5.5-14.6) months. The median (IQR) interval between consecutive unsuppressed viral load measurements was 3.2 (2.5-5.4) months.
Most second-line regimens included didanosine as one of the NRTIs (108 of 153; 71%). Other NRTIs included ZDV (66%), 3TC (25%); d4T (21%); abacavir (13%), and tenofovir (1%). The “third drug” in the regimen was LPV/r for 74% of children.
After adjustment for age at ART initiation, gender and treatment duration, children with more severe or progressive disease from the time of failure (higher viral load, CD4% <25 at switch, CD4% decline >1 percentage point per month between switch date and preceding visit) were more likely to be switched, while taking a PI-based initial regimen was negatively associated with switch (aHR: 0.40; 95% CI: 0.17 to 0.91) (Table 4). Failure to initially attain viral load <400 copies per milliliter after starting ART was not associated with switch in univariable or multivariable analysis. (aHR: 1.02; 95% CI: 0.52 to 1.99).
This study reports in detail on confirmed VF and switching in children on ART in a large African multicenter study where routine viral load monitoring was available. One in 5 children had met the analysis definition of confirmed VF by 3 years on ART. Baseline viral load >1 million copies per milliliter, use of either NVP, or RTV as a sole PI, and PMTCT exposure independently predicted failure. Less than half of children with ≥1 year of follow-up after failure were switched, with a median interval between failure and switch of 5.7 months. Across all sites, current poor immunologic and virologic status together with being on an NNRTI-based regimen favored switch.
Time to VF
Previous studies from Thailand and Uganda with all children on NNRTI-based regimens and failure defined using a single viral load measurement, reported similar proportions of children with VF at 12 months on ART as we report at 36 months using confirmed measurements.5,6 Similarly, a recent cohort study found the frequency of consecutive viral load measurements >400 copies per milliliter among 116 children with follow-up ≥6 months to be 17%.8 Nevertheless, the cumulative probability of a single elevated viral load measurement after 1 year on ART in our study (16%) is similar to the Thai and Ugandan studies. In contrast, prevalence of a single viral load measurement >400 copies per milliliter was 32% at a Tanzanian pediatric clinic, however, 12% of those with VF were on second-line.9 Notwithstanding, our study differs from these with use of PI-based first-line therapy and possible differences in PMTCT exposure and adherence.
For those on NNRTI-based regimens, the confirmation of VF following adherence optimization, as reported in this study, is likely to identify patients who are truly failing with resistance to ≥1 drug in the regimen. For example, an adult study from South Africa showed that 86% of patients with confirmed viral load >1,000 copies per milliliter had therapy-limiting NNRTI mutations.27 Among children with VF in the Thai study, 89% and 97% had major NRTI and NNRTI resistance mutations, respectively. We had no access to resistance testing for children failing therapy, and the prevalence of resistance among children on PI-based regimens with confirmed VF in our context remains unknown.
Comparisons with rich countries are difficult due to differences in age at ART commencement, previous monotherapy or dual therapy, follow-up duration, and first-line regimens. The United Kingdom Collaborative HIV Pediatric Study reported 32% of 595 children having VF after a median follow-up of 3 years, whereas a Dutch cohort of 39 children on nelfinavir-based ART reported 74% VF-free survival after 48 weeks.28,29
First-Line Regimen Choice
The association between NVP-containing regimens and VF concurs with findings from previous pediatric and adult studies.5,6,30,31 It has been suggested that NVP may be underdosed in children taking split adult fixed-dose combination tablets, however, in South Africa, NVP is administered to children as a single drug in syrup/tablet form.5,6 Children may harbor resistance from unrecorded exposure to sdNVP, and subsequent NVP-based ART would be expected to result in poor virologic outcomes.32,33 Although the majority of sdNVP-exposed children in this cohort would have commenced PI-based regimens, it is likely that some initiated NNRTI-based regimens due to site variation in regimen use before national guidelines recommendations. This is supported by both the finding of an association between PMTCT exposure and subsequent failure, despite PMTCT underascertainment, and attenuation of this effect when those without virologic response to ART were excluded. This attenuation is expected as children with NVP resistance would most likely be virologic nonresponders.
Despite our inability to adjust for potential confounding by concomitant tuberculosis and other confounding by indication, our findings suggest that RTV as the sole PI is indeed associated with failure. RTV is unpleasant tasting, associated with poor adherence, and results in a greater accumulation of major PI resistance mutations in comparison with LPV/r.34,35 However, as RTV use would have been more common in children with tuberculosis, we cannot exclude that worse outcomes may have been due to tuberculosis itself or the increased medication burden of ART combined with antituberculous therapy.
Switching to Second-Line
This study reflects clinical practice in a setting with viral load monitoring but no supporting national or WHO guidelines regarding management of children with VF. This is reflected in the low proportion of children switched after failure, and the delay between VF and switch. Heterogeneity in switching practice was also seen in the Collaborative HIV Pediatric Study with nearly half of children with VF being switched before the date of first viral load >1000 copies per milliliter but an equal proportion on first line ≥6 months thereafter.28 In our study, service factors may contribute to the delay; clinical appointments are often 3-monthly with results only available for decision-making at subsequent appointments.
Nevertheless, less than half of children with confirmed VF for ≥1 year were switched, and those who were switched were on a failing regimen for a median of 10 months after the first elevated viral load measurement. In this study, factors other than VF were associated with being switched, including initial regimen, disease severity and progressive immunological decline.
Reluctance to switch a young child failing therapy without thorough assessment of adherence is reasonable in the context of access only to unpleasant second-line regimens, with no third-line/salvage therapy. In this respect, reduced switching of children on PI-based regimens is consistent with knowledge that viral escape is more likely due to poor adherence than resistance.34 Nevertheless, poor access to a wider range of second-line drugs, particularly for children failing first-line PI-based regimens after sdNVP exposure, may result in an understandable reluctance to switch children to a drug to which their virus may be resistant.
If the intention of treatment guidelines is to avoid prolonged viremia, this study suggests the need for more intensive monitoring and adherence interventions soon after a single elevated viral load. The PENPACT1 trial recently reported similar outcomes overall for children switched at viral load measurements of 1000 or 30,000 copies per milliliter, however, highlighted the importance of adherence interventions after initial elevated viral load measures.36,37 In addition, children on NNRTI-based therapy switched at 30,000 copies per milliliter accumulated more NRTI-resistant mutations compared with those switched at 1000 copies per milliliter, suggesting that switching guidelines should be tailored according to regimen.36,37 In large programs, viral load monitoring could additionally be used to manage patient load by stratifying risk. More clinical and adherence input could be given to unsuppressed patients although those with sustained virologic suppression could be managed less intensively.7,38
Strengths and Limitations
This is a large combined cohort of children across many sites providing different levels of care. In addition, viral load measurements were available for >75% of children in care at each 6-monthly duration, and it was possible to use as an outcome confirmed VF rather than a single measure. The large number of infants and inclusion of a PI in first line enabled us to examine the effect on virologic outcome of RTV as the sole PI and LPV/r in comparison to NVP or EFV as components of first-line regimens.
The size of the cohort resulted in a relatively large absolute number of failures and switches, permitting investigation of switching practice.
Despite the study size and the general application of the public health approach to ART provision, the study cohorts, being relatively well resourced and urban, may not be representative of all sites across the region or even South Africa.
Data was collected in the context of routine care in busy clinics. There is limited data on key possible predictors of VF such as tuberculosis coinfection, adherence and PMTCT, and on clinical events. Missing data on other variables limited the range of variables and number of children that could be included in multivariable models. Tuberculosis coinfection not only affects first-line regimen choice, but may impact on virologic outcomes directly or through drug-drug interactions or reduced adherence. We could not explore the extent to which our observed associations with failure were mediated through poor adherence, due to limited data. PMTCT exposure data was only recorded for 40% of children. Furthermore, exact PMTCT regimens were not recorded, so the effect of different regimens could not be examined. The effect of severe clinical disease at ART initiation on VF may have been reduced by combining stage 3 and 4 disease. Due to lack of detailed clinical event data and confounding by indication (with sicker children being preferentially switched), we were unable to determine the clinical consequences of delayed switching.
This study demonstrates the probability of VF in children on ART in South Africa at 3 years to be nearly 20%. The time between failure and switch and low proportion of children switched to second-line in this and other studies supports use of clearer definitions of VF and clinical practice guidelines for managing children with unsuppressed viral load tailored to starting regimen. In addition, access to second-line drugs for PMTCT exposed children failing PI-based ART is important for better pediatric HIV care in the countries where the majority of HIV-infected children reside.
We thank all the children whose data was used in this analysis, as well as their caregivers. We also thank all staff at participating sites for preparation of data contributed to the IeDEA Southern Africa collaboration. Many thanks to Nicola Maxwell for preparing the combined data for analysis, to Morna Cornell and Claire Graber for project management and to Francesca Little for advice on the analysis. Mary-Ann Davies had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors state that they have no conflict of interest.
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APPENDIX: IEDEA SOUTHERN AFRICA STEERING GROUP
Anna Coutsoudis, PMTCT Plus, Durban, South Africa; Diana Dickinson, Gaborone Independent Hospital, Gaborone, Botswana; Brian Eley, Red Cross Children's Hospital, Cape Town, South Africa; Lara Fairall, Free State provincial ARV roll-out, South Africa; Tendani Gaolathe, Princess Marina Hospital, Gaborone, Botswana; Janet Giddy, McCord Hospital, Durban, South Africa; Timothy Meade, CorpMed Clinic, Lusaka, Zambia; Patrick MacPhail, Themba Lethu Clinic, Helen Joseph
Hospital, Johannesburg, South Africa; Lerato Mohapi, Perinatal HIV Research Unit, Johannesburg, South Africa; Margaret Pascoe, Newlands Clinic, Harare, Zimbabwe; Hans Prozesky, Tygerberg Academic Hospital, Stellenbosch, South Africa; Harry Moultrie, Enhancing Children's HIV Outcomes (Harriet Shezi Children's Clinic, Chris Hani Baragwanath Hospital, Soweto); Karl Technau, University of Witwatersrand Paediatric HIV Clinics (Empilweni Clinic, Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa; Gilles van Cutsem, Khayelitsha ART Programme and Médecins sans Frontières, Cape Town, South Africa; Paula Vaz, Paediatric Day Hospital, Maputo, Mozambique; Ralf Weigel, Lighthouse Clinic, Lilongwe, Malawi; Robin Wood, Gugulethu and Masiphumelele ART Programmes, Cape Town, South Africa.
Martin Brinkhof, Matthias Egger, Beatrice Fatzer, Claire Graber, and Olivia Keiser, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Andrew Boulle, Morna Cornell, Mary-Ann Davies, Nicola Maxwell, Landon Myer, and Anna Grimsrud, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.