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Epidemiology and Social

Characteristics, mortality and outcomes at transition for adolescents with perinatal HIV infection in Asia

Bartlett, Adam W.a; Truong, Khan Huub; Songtaweesin, Wipaporn Nataliec; Chokephaibulkit, Kulkanyad; Hansudewechakul, Rawiwane; Ly, Penh Sunf; Lumbiganon, Pagakrongg; Sudjaritruk, Tavitiyah; Nguyen, Lam Vani; Do, Viet Chauj; Kumarasamy, Nagalingeswarank; Nik Yusoff, Nik Khairulddinl; Kurniati, Niam; Fong, Moy Siewn; Wati, Dewi Kumarao; Nallusamy, Revathyp; Sohn, Annette H.q; Law, Matthew G.a; Mohamed, Thahira Jamalr

Author Information
doi: 10.1097/QAD.0000000000001883
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Abstract

Introduction

Accessibility to effective antiretroviral therapy (ART) has shifted the paradigm of HIV infection from a terminal illness to a chronic condition [1]. Infants with perinatally acquired HIV (PHIV) are surviving into adolescence and beyond, which brings with it the challenges of managing a chronic disease during a complex adolescent period of physical, psychological and social change [2]. Perinatally HIV-infected adolescents (PHIVAs) are subject to long-term exposure to potentially harmful processes related to life-long HIV infection, including direct viral cytopathic effects, chronic inflammation, immune-mediated phenomena and effects from ART [3]. The complex interplay of physiologic processes associated with HIV infection and its therapy in the context of adolescence makes this cohort susceptible to poor outcomes [4], and ongoing epidemiologic studies are integral to inform HIV healthcare providers how to optimize the management of PHIVA.

Characteristics and treatment outcomes of children age more than 12 years with PHIV from the TREAT Asia Pediatric HIV Observational Database (TApHOD) cohort of IeDEA Asia-Pacific have been previously reported, which included data up to 2011 [5]. This study aims to provide an update and additional analyses on the characteristics, mortality and outcomes of PHIVA from the TApHOD cohort incorporating data up to 2016 and an adolescent age range of 10–19 years to reflect the WHO adolescent age group and facilitate comparison with other regional cohorts. Specifically assessing the characteristics of PHIVA as they enter adolescence and the impact on PHIVA mortality, the trends in combination ART (cART) across adolescence, the characteristics of those reaching transition to adult HIV services and outcomes at time of transition based on age at cART initiation.

Materials and methods

Study population

Details of the TApHOD cohort have been previously reported [6]. In brief, as of December 2016, there were 16 study sites across six countries in Asia (Cambodia=1, India=1, Indonesia=2, Malaysia=4, Thailand=5 and Vietnam=3) that collect data relating to HIV care, which are transferred to The Kirby Institute (University of New South Wales, Sydney, Australia) for data management and statistical analysis. For this study, any individual 10–19 years of age with PHIV who received care at a TApHOD site through to December 2016 was included. Ethics approval was obtained through the human research ethics committees at the participant sites, The Kirby Institute and the coordinating centre at TREAT Asia/amfAR (Bangkok, Thailand).

Definitions

The adolescent age range was defined as 10–19 years and childhood age range as less than 10 years. Adolescent entry was defined as their 10th birthday or age at first clinic visit for children who had their first clinic visit after their 10th birthday. ART was defined as treatment with any antiretroviral agent. cART was defined as a combination of at least three antiretroviral agents, consisting of either three nucleoside reverse transcriptase inhibitors (NRTIs) or at least three antiretroviral agents from at least two different drug classes. First cART was defined as the initial cART regimen. A switch to second cART was defined as a switch in cART that involved either a change in antiretroviral drug class; or the addition of a new antiretroviral drug class; or a change in at least two antiretroviral drugs. A suppressed HIV viral load was defined as less than 400 copies/ml, immune deficiency as a CD4+ cell count of less than 500 cells/μl and severe immune deficiency as a CD4+ cell count less than 200 cells/μl. Transition to an adult HIV service was determined by the participating site reporting transfer to an adult HIV clinical site, or transfer to any other site at least 16 years of age. Loss to follow-up (LTFU) was determined by either participant sites reporting LTFU or a more than 12-month absence of data from the date of last data transfer from participating sites. Weight-for-age z scores (WAZ) and height-for-age z scores (HAZ) were calculated using WHO 1977 Standards [7] and WHO 2007 Child Growth Standards [8,9], respectively.

Statistical analysis

Descriptive analyses were used to report the demographic, immunologic, virologic and clinical characteristics of PHIVA at adolescent entry and transition. For HIV viral load, CD4+ cell count and growth parameters (WAZ and HAZ), observations that were closest to the respective time points within a 12-month window period were taken. If the date of HIV diagnosis was not available or if the date of HIV diagnostic testing was after study enrolment or ART initiation, then the earliest date available (either study enrolment or ART initiation) was considered the date of HIV diagnosis. Only the event with the highest WHO clinical stage experienced was recorded for each individual. Age at disclosure, LTFU and death were specified. The proportion of PHIVA on first or at least second (subsequent) cART regimen across adolescence were analysed on an intention-to-treat basis, with death, LTFU and transition considered censoring events. Mortality rates were determined by survival analysis with person-year observations calculated from adolescent entry to death, LTFU, transition, last reported clinic visit (if occurring at < 20 years of age) or 19.9 years of age (if remaining in active care ≥20 years of age). A competing risk regression analysis (Fine and Gray method) [10], with LTFU as a competing event, was used to determine associations between characteristics at adolescent entry and mortality. Subdistribution hazard ratios (SHRs) were calculated for covariates, including sex; orphan status; primary caregiver; clinic setting; HIV viral load; CD4+ cell count; tuberculosis (TB) infection; HAZ; WAZ; having experienced a WHO clinical event, ART adverse event or hospitalization; and age at cART initiation and cART regimen at adolescent entry. Covariates with a P value of less than 0.1 on univariate analysis were included in a multivariate analysis and adjusted SHR (aSHR) calculated. The multivariate analysis was conducted in a stepwise fashion maintaining covariates that retained a P value of less than 0.05. In analysing outcomes at transition, individuals were stratified by age at cART initiation (<5, 5–9, ≥10 years), the Kruskal–Wallis test was used for continuous variables, and chi-square or Fisher's exact test used for categorical variables. Unknown or missing data were included in the analyses as a separate category within each variable. Statistical analyses were performed using Stata, version 14.2 (StataCorp LP, College Station, Texas, USA).

Results

Characteristics of perinatally HIV-infected adolescent cohort

As of December 2016, there were 5647 children and adolescents with PHIV who had received care within the TApHOD network. Of these, 3448 were aged 10–19 years and included in the study, with adolescent data ranging from 2001 to 2016. The median age at HIV diagnosis for the PHIVA cohort was 5.5 years [interquartile range (IQR) 2.9–8.4]. cART had been commenced in 3314 PHIVA at a median age of 7.2 years [IQR 4.6–9.9]. A second cART regimen had been started in 1202 PHIVA at a median age of 10.7 years [IQR 7.5–13.9]. For those enrolled in care by their 10th birthday (n = 2758), the median age at HIV diagnosis was 4.7 years [IQR 2.4–6.9] and at cART initiation was 6.4 years [IQR 4.1–8.5]. For those enrolled in care after their 10th birthday (n = 690), the median age at HIV diagnosis was 10.8 years [IQR 9.1–12.3] and at cART initiation was 11.5 years [IQR 10.4–13.1]. There were 163 PHIVA LTFU [median age 15.4 years (IQR 12.4–17.4)], 119 PHIVA who died [median age of 13.0 years (IQR 11.1–15.8)] and 2328 PHIVA in active care [median age 13.8 years (IQR 12.0–15.9)]. The median age at HIV disclosure was 12.2 years [IQR 10.5–13.7]. Overall, 644 PHIVA had transitioned to an adult HIV service at a median age of 17.9 years [IQR 16.8–19.6].

Table 1 summarizes the characteristics of PHIVA at time of adolescent entry and transition. For those with available data, unsuppressed HIV viral loads were reported in 624 out of 2279 (27.4%) of PHIVA at adolescent entry and 76 out of 492 (15.4%) at the time of transition, while a CD4+ cell count of less than 500 cells/μl was reported in 1152 out of 3294 (35.0%) of PHIVA at adolescent entry and 227 out of 583 (38.9%) at transition. A WHO stage III/IV clinical event was experienced in 51.1% by adolescent entry and 53.4% reaching transition, while an ART adverse event was encountered in 14.3% by adolescent entry and 20.8% reaching transition. Hospitalization was required in 19.4 and 20.8% of individuals due to a WHO clinical event by adolescent entry and transition, respectively; and 1.9 and 3% of individuals as a result of an ART adverse event by adolescent entry and transition, respectively. At adolescent entry, there were 706 (20.5%) PHIVA who were ART naive, 49 (1.4%) on monotherapy or dual therapy, 2124 (61.6%) on their first cART regimen and 569 (16.5%) on at least their second cART regimen. For those who reached transition, seven (1.1%) PHIVA remained ART naive, 379 (58.9%) continued their first cART regimen and 258 (40.1%) were on at least their second cART regimen.

Table 1
Table 1:
Characteristics of perinatally HIV-infected adolescents at time of adolescent entrya and transition.

Perinatally HIV-infected adolescent mortality

The overall mortality rate was 0.71 per 100 person-years [95% confidence interval (95% CI) 0.60–0.85]. For those enrolled in care by their 10th birthday, the mortality rate was 0.47 per 100-person years (95% CI 0.37–0.61), while for those enrolled in care after their 10th birthday, the mortality rate was 1.6 per 100-person years (95% CI 1.2–2.1). On multivariate analysis, the following characteristics at adolescent entry were found to be significant risk factors for adolescent mortality: HIV viral load at least 1000 copies/ml [1000–9999 copies/ml aSHR 3.2 (95% CI 1.2–8.4); ≥10 000 copies/ml aSHR 2.9 (95% CI 1.5–5.5)]; CD4+ cell count less than 500 copies/ml [200–499 cells/μl aSHR 3.1 (95% CI 1.5–6.1)]; < 200 cells/μl aSHR 11.2 (95% CI 6.1–20.7)]; HAZ less than −2 [aSHR 1.8 (95% CI 1.1–3.0)]; WAZ less than −2 [aSHR 2.7 (95% CI 1.5–4.7)]; prior or current WHO stage III/IV clinical event [aSHR 2.3 (95% CI 1.5–3.6)]; prior or current hospitalization [aSHR 1.7 (95% CI 1.1–2.5)]; and being on at least second cART regimen irrespective of age at initial cART commencement [initial cART at age < 5 years with at least second regimen at adolescent entry aSHR 5.0 (95% CI 1.04–23.9); initial cART at age 5–9 years with at least second regimen at adolescent entry aSHR 4.7 (95% CI 1.03–21.9)] (Table 2).

Table 2
Table 2:
Factors at adolescent entrya associated with mortality.

Trends in combination antiretroviral therapy across adolescence

Figure 1 shows the relative proportion of PHIVA on first or subsequent (at least second) cART regimen across adolescence. At age 10 years (n = 3448), there were 2117 (61.4%) PHIVA on their first cART regimen, 637 (18.5%) on their subsequent cART regimen and 694 (20.1%) who had not commenced cART (i.e. either ART naive or receiving mono or dual therapy). For those who remained in active paediatric care through to age 19 years (n = 544), there were 281 (51.7%) PHIVA who had continued their first regimen, 258 (47.4%) on a subsequent cART regimen and five (0.9%) who had not received cART.

Fig. 1
Fig. 1:
Proportion of PHIVA on combination antiretroviral therapy across adolescence.cART, combination antiretroviral therapy; PHIVA, perinatally HIV-infected adolescent; subsequent cART regimen, ≥ second cART regimen.

PHIVA outcomes at transition based on age at combination antiretroviral therapy initiation

Of the 644 PHIVA who had transitioned out of paediatric care, 39 (5.6%) had commenced cART at age less than 5 years, 309 (48.0%) at age 5–9 years, 289 (44.9%) at age at least 10 years and seven (1.1%) had not commenced cART prior to transition. When stratified by age at cART initiation (<5, 5–9, ≥10 years), there was a significantly higher proportion of PHIVA who had commenced cART at age less than 5 years with a suppressed HIV viral load (P = 0.048) and CD4+ cell count at least 500 cells/μl (P = 0.003) at the time of transition (Table 3). In addition, there was a significantly lower proportion of those commencing cART at age less than 5 years on their first cART regimen at the time of transition (P = 0.046) (Table 3). There were no significant differences in growth parameters, or history of a WHO clinical event or ART adverse event by time of transition.

Table 3
Table 3:
Outcomes at time of transition stratified by age at cART initiation.

Discussion

This study provides key insights into the characteristics of Asian PHIVA as they entered adolescence and the impact of their health on subsequent mortality, as well as outcomes for those surviving to transition to adult services. The delay in HIV diagnosis (median age 5.5 years) and cART initiation (median age 7.2 years) highlights issues regarding access to HIV diagnostics and treatment for infants in the Asian region. Given current standards of care advocate early infant diagnosis and cART initiation irrespective of immunologic and virologic status [11,12], these figures support ongoing efforts to strengthen the continuum of care from prevention of mother-to-child transmission programmes to paediatric HIV health services in Asia. These delays in HIV diagnosis and cART initiation contributed to the substantial cumulative morbidity encountered by our study cohort by the time they reached adolescence, with more than half having experienced a WHO stage III/IV event. In addition, at least one in three were immune deficient at adolescent entry, highlighting the negative impact delayed diagnosis and cART initiation has on immune status [13].

The mortality rate of 0.71 per 100 person-years calculated for our PHIVA cohort is similar to that reported in a South African PHIVA cohort (0.80 per 100 person-years) [14], less than that reported in a Ugandan adolescent cohort (3.65 per 100 person-years) [15], and more than that reported in PHIV youths from a combined Paediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 1074 cohort (0.4 per 100 person-years) [16]. These comparisons demonstrate the context-specific nature of HIV outcomes, and the influence of health infrastructures on access to HIV diagnostics and ART, as well as long-term HIV health maintenance throughout adolescence [17].

Our results demonstrated having a HIV viral load of more than 1000 copies/ml, a CD4+ cell count of less than 500 cells/μl, poor growth, a history of a WHO stage III/IV clinical event or hospitalization, and receiving at least their second cART regimen at adolescent entry to be associated with adolescent mortality. Aside from cART regimen, these features are indicative of poor disease control, and demonstrate the detrimental effects delayed HIV diagnosis and cART initiation in childhood has on longer term outcomes. The risk factors of uncontrolled viraemia and poor immune status on mortality are reflected in studies conducted in Thai national cohorts [18,19], and the majority of deaths in PHIV youths from the combined PHACS AMP and IMPAACT 1074 cohort occurred in the context of a HIV viral load at least 400 copies/ml and/or CD4+ cell count less than 200 cells/μl [16]. The association between receiving at least second cART regimen and adolescent mortality could reflect issues with ART resistance, adherence, and/or intolerances, leading to poorer outcomes, and supports the identified need to develop and implement strategies to optimize ART adherence [20,21], as well as ongoing efforts to optimize cART durability and tolerability. The fact that those who were cART naive at adolescent entry were not found to be at a higher risk of mortality may be due to them having less advanced disease.

Currently, there are limited epidemiologic data on outcomes for PHIVA reaching transition [22,23]. For those who survived to transition, half had experienced a WHO stage III/IV event, one in five had an ART adverse event and at least one in five had required hospitalization. In addition to the morbidity encountered, at least one in three were immune deficient. These immunologic outcomes are similar to that reported in Canada [24], and better than that reported in the UK (where over half were immune deficient) [25]. This is concerning given the challenges to the care continuum that are encountered at the time of transition from paediatric to adult HIV services, and the negative impact this can have on the HIV health of the young adult. To add to the challenges surrounding transition is retention in care [24,26]. The median age of LTFU in this study was 15.4 years, which is leading into the crucial period of transition, and re-enforces the need for youth-specific engagement strategies to ensure retention in care and to navigate the transition process [27]. Those who had commenced cART at age less than 5 years demonstrated better virologic and immunologic outcomes at the time of transition, which supports the role of early cART initiation. However, this subgroup was also most likely to undergo a regimen switch. The fact there was no significant difference at transition with regards to disease or treatment-related morbidity based on age at cART initiation could reflect a survival bias in that those surviving to transition are those with relatively stable disease. It is also possible that the 5-year categorizations may be too broad to detect a difference.

Almost half of those who had remained in active paediatric care through to 19 years of age had switched to at least their second cART regimen. These results signify the amount of ART exposure across multiple drug classes, either due to treatment failure or ART intolerances, thereby narrowing future therapeutic options throughout adulthood, and highlight the need for better access to newer antiretroviral agents in resource-limited settings [28]. Given the move towards commencing cART on all children with PHIV as early as possible and the complexities in choosing subsequent cART regimens [29], these figures, in conjunction with the association of receiving at least second cART and PHIVA mortality, highlights the importance of continuing evaluations on the durability and tolerability of first-line cART options.

Limitations of this study include inconsistent reporting and variable access to laboratory testing within sites over time and across sites leading to incomplete data. This could lead to transition events being unreported and classified as LTFU, unascertained mortality among those LTFU and the inability to determine whether regimens switches were based on treatment failure, ART intolerances or regimen simplification. There is also the potential for a survival bias associated with reporting mortality rates only for those who survived to adolescence and not the greater PHIV cohort.

In conclusion, this study highlights the substantial cumulative morbidity experienced by Asian PHIVA by adolescent entry and transition, and emphasizes the importance of virologic, immunologic and clinical disease control, as well as first-line cART durability/tolerability to minimise adolescent mortality. Commencing cART at age less than 5 years provided the best virologic and immunologic outcomes for PHIVA at transition, though they more likely to require to a regimen switch. Almost half of PHIVA remaining in paediatric care towards the end of adolescence were on at least their second cART regimen, providing impetus for ongoing efforts to optimize the durability and tolerability of cART regimens to preserve future therapeutic options, particularly in the era of early cART initiation.

Acknowledgements

A.W.B., T.H.K., W.N.S., K.C., A.H.S., M.G.L. and T.J.M. conceived and designed the analysis. A.W.B. conducted the data analysis. All authors reviewed the data analysis and were involved in manuscript preparation.

The TREAT Asia Pediatric HIV Network: PS Ly*, and V Khol, National Centre for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; J Tucker, New Hope for Cambodian Children, Phnom Penh, Cambodia; N Kumarasamy*, and E Chandrasekaran, YRGCARE Medical Centre, CART CRS, Chennai, India; DK Wati*, D Vedaswari and IB Ramajaya, Sanglah Hospital, Udayana University, Bali, Indonesia; N Kurniati*, and D Muktiarti, Cipto Mangunkusumo - Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; SM Fong*, M Lim and F Daut, Hospital Likas, Kota Kinabalu, Malaysia; NK Nik Yusoff*‡, and P Mohamad, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; TJ Mohamed*, and MR Drawis, Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; R Nallusamy*, and KC Chan, Penang Hospital, Penang, Malaysia; T Sudjaritruk*, 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*, P Ounchanum, S Denjanta, and A Kongphonoi, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; P Lumbiganon*†, 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*, 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*, K Lapphra, W Phongsamart, and S Sricharoenchai, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;

KH Truong*, QT Du and CH Nguyen, Children's Hospital 1, Ho Chi Minh City, Vietnam; VC Do*, TM Ha, and VT An Children's Hospital 2, Ho Chi Minh City, Vietnam;

LV Nguyen*, DTK Khu, AN Pham, and LT Nguyen, National Hospital of Pediatrics, Hanoi, Vietnam; ON Le, Worldwide Orphans Foundation, Ho Chi Minh City, Vietnam;

AH Sohn*, JL Ross, and C Sethaputra, TREAT Asia/amfAR – The Foundation for AIDS Research, Bangkok, Thailand; DA Cooper, MG Law*, and A Kariminia, The Kirby Institute, UNSW Australia, Sydney, Australia; *TApHOD Steering Committee member; † Current Steering Committee Chair; ‡ co-Chair.

The TREAT Asia Pediatric HIV Observational Database is an initiative of TREAT Asia, a programme of amfAR, The Foundation for AIDS Research, with support from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Cancer Institute, National Institute of Mental Health, and National Institute on Drug Abuse as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907). The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Australia. AWB received support from an Australian Government Research Training Program Scholarship. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the governments or institutions mentioned above.

Conflicts of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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Keywords:

adolescents; HIV; mortality; transition

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