Maintaining effective antiretroviral therapy (ART) is one of the key challenges to managing children and adolescents living with HIV, with poor treatment adherence and drug resistance representing major threats to its success. HIV viral load testing is the preferred method to monitor response to ART and is an important tool in identifying issues with treatment adherence and drug resistance.1 Assessing virologic response to ART is also an integral component of the UNAIDS “90-90-90” strategy,2 which calls for over 3-million infants, children, and adolescents living with HIV to have access to ART and HIV viral load testing.3 If these targets set out in the UNAIDS strategy are to be accomplished, a comprehensive understanding of the burden of virologic failure and associated factors is imperative.
With efforts to expand access to ART and HIV viral load testing, the understanding of virologic failure is evolving.4–6 Among pediatric studies published to date, virologic failure has been reported in 25%–34% of children and adolescents receiving ART.6–8 This highlights the need to better understand the burden of virologic failure in pediatric cohorts to guide development and implementation of targeted interventions to optimize the durability of ART regimens and HIV outcomes, as well as reach the UNAIDS target of viral suppression in 90% of those on ART by 2020. This study aims to describe the incidence of virologic failure and its associated factors within the TREAT Asia pediatric HIV Observational Database (TApHOD) cohort, a regional study in South and Southeast Asia.
Study Population and Settings
TApHOD is a regional observational database incorporating 16 pediatric HIV services across 6 countries in Asia (Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam). Information relating to patient demographics, clinical features, laboratory results, and treatment are collected during routine HIV care and transferred to the Kirby Institute, University of New South Wales, Sydney, NSW, Australia, for data management and statistical analysis. Further details of the study cohort have been previously reported.9
HIV-Infected children and adolescents (<20 years of age) who initiated care at a TApHOD site between January 1, 2005, and December 31, 2014, were included if they: (1) received at least 6 months of continuous combination ART (cART); (2) had a documented suppressed viral load (<400 copies per milliliter) 5–12 months after cART initiation; and (3) had at least one HIV viral load after virologic suppression before the age of 20 years. Data for these patients to the end of 2016 were included to allow sufficient time for HIV viral load testing after virologic suppression. Ethics approvals were obtained through the human research ethics committees at the respective sites, the Kirby Institute, and the coordinating center at TREAT Asia/amfAR (Bangkok, Thailand).
Continuous cART was defined as an antiretroviral regimen consisting of at least 3 agents with no more than a 2-week treatment interruption. Virologic suppression was defined as receiving 6 months of continuous cART in conjunction with a documented HIV viral load of <400 copies per milliliter 5–12 months after commencing continuous cART. Virologic failure was defined as at least 1 HIV viral load of ≥1000 copies per milliliter after virologic suppression. Early virologic failure was defined as virologic failure ≤12 months from initial virologic suppression, whereas late virologic failure was defined as virologic failure >12 months after initial virologic suppression. A viral blip was defined as a single detectable viral load of 400–999 copies per milliliter that was preceded and followed by a suppressed viral load (<400 copies per milliliter). Loss-to-follow-up (LTFU) was determined by either documentation of LTFU by the treating site or a >12-month absence of reported clinical data before the date of the site's last data transfer. Anemia was defined as hemoglobin ≤10.0 g/dL.10 Weight-for-age z scores (WAZ) were determined using World Health Organization (WHO) 1977 Standards,11 and height-for-age z scores were determined using WHO 2007 Child Growth Standards.12,13
Descriptive statistics were used to report the demographic, immunologic, virologic, and clinical characteristics of patients at time of cART initiation and virologic suppression. Descriptive characteristics were compared between the included population and those excluded who had received ≥6 months of continuous cART with no accompanying HIV viral load testing 5–12 months after cART initiation, and the Wilcoxon–Mann–Whitney test was used to evaluate statistically significant differences in nonparametric continuous variables. A time-to-event analysis, with LTFU and death as competing events, was used to determine the cumulative incidence of virologic failure stratified by age at time of virologic suppression. A competing risk regression analysis (Fine and Gray method),14 with LTFU and death as competing risks, was used to determine the subdistribution hazard ratio (sHR) and adjusted sHR (asHR) for factors at time of virologic suppression associated with (1) early virologic failure and (2) late virologic failure. Covariates included sex, age, orphan status, primary caregiver, type of clinic setting, CD4%, WHO clinical stage, viral blip, WAZ, height-for-age z score, hepatitis B/C infection, tuberculosis (TB) infection (diagnosed within the preceding 6 months), cART regimen, and calendar year. Early virologic failure was also evaluated as a covariate for late virologic failure. The period of observation for virologic failure for each patient started the date virologic suppression was achieved and finished when the patient either experienced a competing event (LTFU or death) or had their last clinic visit. Covariates with a P value of <0.1 on univariate analysis were included in multivariate analyses. Multivariate analyses were conducted in a stepwise fashion, maintaining covariates that retained a P value of <0.05. All statistical analyses were performed using Stata, version 14.2 (StataCorp LP, College Station, TX).
Of the 4601 HIV-infected children and adolescents who were enrolled in care at participating sites between January 1, 2005, and December 31, 2014, a total of 1015 (22.1%) achieved virologic suppression and had subsequent viral load testing, and were included in the analysis. Their characteristics at the time of cART initiation and virologic suppression are summarized in Table 1. The median age at cART initiation was 6.1 [interquartile range (IQR) 3.0–9.3] years and virologic suppression 6.9 (IQR 3.8–10.3) years. The median time to achieve virologic suppression was 6.4 (IQR 5.8–8.8) months. The median duration of continuous cART was 6.1 (IQR 3.7–8.6) years. Approximately 90% of cART regimens included nonnucleoside reverse transcriptase inhibitors (NNRTIs) at cART initiation and at virologic suppression. Of the 906 patients receiving NNRTI-based regimens at virologic suppression, 10 (1.1%) had either a protease inhibitor (PI)-based or other initial cART regimen. Of the 103 patients receiving PI-based regimens at virologic suppression, 22 (21.4%) had either an NNRTI-based or other prior cART regimen. All PI-based regimens were boosted. During the period between cART initiation and virologic suppression, there were improvements in WAZ (34.2% vs 26.7% with WAZ ≥−1), prevalence of anemia (25.6% vs 7.6%), and overall median CD4% (11.0% vs 21.1%).
Of the 3586 children and adolescents who were excluded: 845 (23.6%) received <6 months of continuous cART; 2404 (67%) received ≥6 months of continuous cART but did not have HIV viral load testing 5–12 months after cART initiation; 284 (7.9%) received ≥6 months of continuous cART but had unsuppressed HIV viral loads 5–12 after cART initiation; and 53 (1.5%) received ≥6 months of continuous cART and achieved virologic suppression within 5–12 months but did not have subsequent HIV viral load testing. For the 2404 who were excluded on the grounds of having received ≥6 months continuous cART but no accompanying HIV viral load testing 5–12 months after cART initiation, comparison with the included population showed no difference in sex (47.4% vs 51.2% females), initial cART regimen (93.6% vs 89.3% with NNRTI-based cART), median CD4% at cART initiation (11.5% [IQR 4.0–18.2] vs 11% [IQR 4.6–17], P = 0.21), or WHO clinical stage at cART initiation (34.3% vs 37.9% with WHO clinical stage III/IV). However, this excluded subpopulation had a lower median age at cART initiation (4.5 [IQR 2.2–7.4] years vs 6.1 [IQR 3–9.3] years, P < 0.001); a higher proportion from Vietnam (56.7% vs 12.2%), Indonesia (10.2% vs 0.8%), and India (4.1% vs 0.3%); and a higher proportion from urban clinic settings (77.2% vs 45.1%) compared with the included population. For the 284 who were excluded because despite having received ≥6 months continuous cART they had unsuppressed HIV viral loads 5–12 months after cART initiation, there was a higher proportion of males (59.9% vs 48.8%) and those with WHO clinical stage III/IV disease at cART initiation (44.4% vs 37.9%), and a lower median age at cART initiation (4.0 [IQR 1.6–8.1] years vs 6.1 [IQR 3–9.3] years, P < 0.001) compared with the included population. This excluded subpopulation also had a higher proportion from Malaysia (19.4% vs 10.9%) and Vietnam (22.9% vs 12.2%), and a lower proportion from Thailand (31.7% vs 47.2%) compared with the included population. There was no difference in the initial cART regimen (88.4% vs 89.3% NNRT-based cART), median CD4% at time at cART initiation (11.0% [IQR 4.0–18.5] vs 11.0% [IQR 4.6–17], P = 0.88), or the proportion of those being managed in an urban clinic setting (49.3% vs 45.1%) between this excluded subpopulation and the included population.
Of the 1015 who achieved virologic suppression and had subsequent viral load testing, there were 182 (17.9%) patients who experienced at least one virologic failure event. The median time to virologic failure was 24.6 (IQR 12–54) months. The crude first virologic failure rate was 3.3 [95% confidence interval (CI): 2.9 to 3.9] per 100 person-years. The incidence of virologic failure in the study cohort gradually declined throughout the course of cART (Fig. 1). The cumulative incidence of a first virologic failure event progressively increased as the age at virologic suppression increased (Fig. 2). Of the 182 patients experiencing a virologic failure event, 101 (55.5%) would eventually achieve documented virologic suppression.
There were 38 patients who experienced an early virologic failure event, which represented 20.9% of those who experienced any virologic failure event. On regression analysis, there were no specific characteristics at virologic suppression identified as factors associated with early virologic failure (Table 2). There were 156 patients who experienced a late virologic failure event, representing 85.7% of subjects who experienced any virologic failure event. Of these, 12 (7.7%) had also experienced an early virologic failure event. On multivariate regression analysis, the following characteristics at virologic suppression were associated with late virologic failure: age >3 years compared with age <3 years (3–4 years asHR 2.9 [95% CI: 1.4 to 5.9]; 5–9 years asHR 4.0 [95% CI: 2.0 to 7.8]; 10–14 years asHR 6.3 [95% CI: 3.2 to 12.2]; and 15–19 years asHR 7.9 [95% CI: 3.3 to 18.8]); receiving care in a mostly rural clinic setting compared with an urban setting (asHR 3.6 [95% CI: 1.6 to 8.0]); TB infection (asHR 3.8 [95% CI: 1.9 to 7.6]); receiving a PI-based cART regimen compared with an NNRTI-based regimen (asHR 2.4 [95% CI: 1.5 to 3.9]); and having experienced an early virologic failure event (asHR 2.6 [95% CI: 1.4 to 4.7]) (Table 2).
This study presents valuable findings regarding the burden of virologic failure and associated risk factors in Asian children and adolescents. In particular, 18% of our cohort developed virologic failure after virologic suppression over a median of 6.1 years on continuous cART. Factors at virologic suppression associated with virologic failure after 12 months included older age, a history of TB infection, receiving a PI-based regimen, and treatment in a mostly rural clinic setting. In addition, those who experienced virologic failure within 12 months of virologic suppression were more likely to experience subsequent virologic failure.
The proportion of children and adolescents experiencing virologic failure in our study cohort is less than the 25%–34% reported in other pediatric cohorts, with a median age at ART initiation ranging from 4.6 to 9.3 years.6–8 However, unlike the other studies, the estimates of virologic failure in our analysis incorporated a cohort of children and adolescents who had confirmed virologic suppression. This is likely to select out a subset of patients with a greater likelihood of treatment adherence, as well as reduce the impact of transmitted or prior drug resistance on virologic outcomes. The median time to virologic failure in our cohort was 2 years, and there was a pattern of decreasing incidence of virologic failure over time. This is consistent with results from a Thai pediatric cohort that reported a median time to virologic failure of 22 months and a decreasing trend in rate of virologic failure throughout the course of cART.4
The most striking risk factor for late virologic failure was the age at which virologic suppression was initially achieved. Those who achieved virologic suppression >3 years of age were more likely develop virologic failure compared with those <3 years of age, with adolescents (aged 10–19 years) demonstrating the highest risk group. The better outcomes for the youngest cohort may reflect better engagement through the continuum of care from maternal and antenatal services to pediatric services. As for adolescents, our findings add further weight to the growing body of evidence regarding poorer virologic outcomes for adolescents, which has been demonstrated irrespective of the resource setting.15–18 Given the median age at cART initiation of 6.1 years in our study, in a cohort where at least 86.7% acquired HIV perinatally, there have been considerable delays in commencing cART for our current surviving cohort of children with perinatally acquired HIV infection. This not only resulted in poorer virologic outcomes as demonstrated by our study but also has implications for the degree of immune suppression and severity of clinical disease, which has been demonstrated to impact treatment outcomes in other studies.19,20 These results further reiterate the importance of early diagnosis of perinatal HIV infection and prompt cART initiation to optimize immunologic, virologic, and clinical outcomes.
Studies evaluating the association between TB coinfection and late virologic failure have produced variable results. Our analysis, which reported a higher risk of virologic failure associated with TB, is consistent with previous observational data from pediatric cohorts in Mozambique and Uganda.21 However, in a combined cohort of children, adolescents, and adults from Swaziland, TB coinfection was not associated with virologic failure.22 In addition, a systematic review including 13 adult studies on the impact of TB treatment on virologic failure found inconclusive evidence regarding the impact of TB treatment on virologic failure, which was largely due to the heterogeneity in definitions for virologic failure.23 HIV/TB coinfection continues to be a significant global health concern, and given current WHO recommendations for concurrent ART and TB therapy to improve mortality outcomes,24 our results support the need for further longitudinal studies on the virologic outcomes for children and adolescents with HIV/TB coinfection to identify potential areas to refine management.25
Our finding of the association between boosted PI-based therapy and late virologic failure is not in keeping with previous pediatric studies. In a rural Tanzanian cohort, a higher likelihood of virologic failure was associated with NNRTI-based compared with PI-based therapy6; while a South African study found unboosted ritonavir, but not boosted ritonavir, containing cART regimens to have a higher likelihood of virologic failure compared with efavirenz containing ART regimens.5 The higher risk of virologic failure for those receiving PI-based therapy demonstrated in our cohort may reflect the higher likelihood of using PI-based regimens as 2nd line in our study cohort. Of those receiving a PI-based regimen at virologic suppression, 20% had initially commenced an NNRTI-based or other type of cART regimen, whereas only 1% of those who were receiving an NNRTI-based cART regimen at virologic suppression had initially commenced a PI-based or other type of cART regimen. Therefore, those who were on a PI-based regimen at virologic suppression in our study were more likely to have a complex history of ART exposure and/or possible issues with previous treatment adherence.
The differences in virologic outcomes based on type of clinic setting demonstrated in our study identify the complex nature of HIV health infrastructures, and the need for pediatric expertise across the spectrum of services from centrally located specialized facilities to local clinics. This is particularly important given the shift to decentralize HIV services, which requires additional considerations regarding transfer of care, supply and access to effective cART regimens, and local clinic resources with adequate staffing and support from specialized centers through accessible referral systems.
Those who experienced an early virologic failure event in our cohort were shown to be at a 2-fold higher risk of a subsequent virologic failure event. This could reflect ongoing issues with ART adherence or drug resistance and the difficulties in implementing interventions to improve virologic outcomes. The reason no specific characteristics were identified as factors associated with early virologic failure could be due to the small number of early virologic failure events according to our criteria.
This study has several limitations. First, clinical practice regarding HIV viral load testing has not been uniform across the region, with a considerable proportion either not having any HIV viral load results or not being tested within the 5–12-month study inclusion period after cART initiation. Those with viral load testing may have either come from higher resourced clinics or have been selected for testing due to concerns over adherence. Consequently, we may have overestimated or underestimated the burden of virologic failure within our cohort. Second, our criteria for virologic failure included only one HIV viral load >1000, which is less stringent than that defined by the WHO (of 2 consecutive HIV viral loads >1000 with optimal ART adherence); however, this was considered a reasonable approach given that we prespecified prior virologic suppression, the prevalent use of NNRTIs in first-line regimens, the frequency of HIV viral load testing in our region during the study period, and previous studies using similar definitions.4,26–28 Third, due to a lack of self- or clinic-reported adherence measures and the lack of HIV resistance testing, we were unable to determine the impact of treatment adherence and drug resistance on virologic failure.
In conclusion, our study showed that approximately 1 in 5 children and adolescents in our Asian cohort who achieved virologic suppression after cART initiation experienced subsequent virologic failure at a median time of 2 years. Older age at cART initiation, a history of TB coinfection, use of PI-based regimens, treatment in rural clinic settings, and early virologic failure were associated with long-term virologic failure. These results suggest that if the targets of the UNAIDS “90-90-90” strategy are to be met in Asia, there needs to be improved capacity for early HIV diagnosis and cART initiation of HIV-exposed infants and children, regular HIV viral load testing, and targeted interventions for complex treatment scenarios, such as adolescents, TB coinfection, extensive ART exposure, and those with a history of poor virologic control. Adequate resource allocation across all clinic settings is integral if such measures to optimize virologic outcomes for children and adolescents living with HIV are achievable.
The TREAT Asia Pediatric HIV Network: P.S. Ly (TApHOD Steering Committee member), V. Khol, and R. Seng, National Centre for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; J. Tucker, New Hope for Cambodian Children, Phnom Penh, Cambodia; N. Kumarasamy (TApHOD Steering Committee member) and E. Chandrasekaran, YRGCARE Medical Centre, CART CRS, Chennai, India; D. K. Wati (TApHOD Steering Committee member), D. Vedaswari, and I.B. Ramajaya, Sanglah Hospital, Udayana University, Bali, Indonesia; N. Kurniati (TApHOD Steering Committee member) and D. Muktiarti, Cipto Mangunkusumo—Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; S.M. Fong (TApHOD Steering Committee member), K.J. Wong, and F.B. Daut, Hospital Likas, Kota Kinabalu, Malaysia; N.K. Nik Yusoff (TApHOD Steering Committee member) (Current Steering Committee Chair) and P. Mohamad, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; T.J. Mohamed (TApHOD Steering Committee member) and M.R. Drawis, Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; R. Nallusamy (TApHOD Steering Committee member) and K.C. Chan, Penang Hospital, Penang, Malaysia; T. Sudjaritruk (TApHOD Steering Committee member), V. Sirisanthana, and L. Aurpibul, Department of Pediatrics, Faculty of Medicine, and Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; R. Hansudewechakul (TApHOD Steering Committee member), P. Ounchanum, S. Denjanta, and A. Kongponoi, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; P. Lumbiganon (TApHOD Steering Committee member), P. Kosalaraksa, P. Tharnprisan, and T. Udomphanit, Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; G. Jourdain, PHPT-IRD UMI 174 (Institut de recherche pour le développement and Chiang Mai University), Chiang Mai, Thailand; T. Puthanakit (TApHOD Steering Committee member), S. Anugulruengkit, W. Jantarabenjakul, and R. Nadsasarn, Department of Pediatrics, Faculty of Medicine and Research Unit in Pediatric and Infectious Diseases, Chulalongkorn University, Bangkok, Thailand; K. Chokephaibulkit (TApHOD Steering Committee member) (Co-Chair), K. Lapphra, W. Phongsamart, and N. Vanprapar, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; K.H. Truong (TApHOD Steering Committee member), Q.T. Du, and T.T. Nguyen, Children's Hospital 1, Ho Chi Minh City, Vietnam; V.C. Do (TApHOD Steering Committee member), T.M. Ha, and V.T. An Children's Hospital 2, Ho Chi Minh City, Vietnam; L.V. Nguyen (TApHOD Steering Committee member), D.T.K. Khu, and L.T. Nguyen, National Hospital of Pediatrics, Hanoi, Vietnam; O.N. Le, Worldwide Orphans Foundation, Ho Chi Minh City, Vietnam; A.H. Sohn (TApHOD Steering Committee member), J.L. Ross, and C. Sethaputra, TREAT Asia/amfAR—The Foundation for AIDS Research, Bangkok, Thailand; D.A. Cooper, M.G. Law (TApHOD Steering Committee member), and A. Kariminia, The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
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