Growth of HIV-Infected Children in the Early Stage of Antiretroviral Treatment: A Retrospective Cohort Study in China

Abstract

Malnutrition and human immunodeficiency virus (HIV)-related complications are commonly seen in HIV-infected children, and these have been shown in high-prevalent areas such as Africa. Antiviral therapy (ART) has notably controlled disease progression, whereas it effectively reverses underweight and growth retardation in HIV-infected children. This study was conducted to evaluate the growth status after initiation of ART in HIV-infected children in China. A retrospective cohort study was conducted based on the National Science and Technology Major Project. HIV-infected children who initiated antiretroviral treatment between January 1st, 2012 and December 31st, 2012 were followed up to December 31st, 2014. Z-scores of height and weight were calculated by WHO Anthro (plus). Linear mixed-effects models were used to model trajectories of weight- and height-for-age Z-scores. Seven hundred forty-four participants enrolled in the study, with 585 participants and 712 participants who had WAZ (weight-for-age Z-score) and HAZ (height-for-age Z-score), respectively, before initiation of ART. Among them, 125 (21.4%) were underweight and 301 (42.3%) were stunted. After treatment, among the 125 underweight children, WAZ improved in 69 patients, regained more than −2 on average. Among the 301 stunted children, HAZ improved in 123 patients, regained more than −2 on average. WAZ improved for the first 6 months by 0.052 units each month and then stabilized, whereas HAZ consistently improved by 0.014 units each month over time. Antiretroviral treatment reversed the adverse effects of HIV to some degree. Early diagnosis and treatment, with an effective nutrition program, is necessary to improve malnutrition further.

Introduction

Until the end of 2014, an estimated 2.6 million children less than 15 years old were human immunodeficiency virus (HIV) positive worldwide. There is no doubt that after HAART, the mortality in children living with HIV has decreased significantly.¹ However, the number of children on treatment is still low. Of the 2.6 million children, one in three is on treatment.² In China, 5824 children received free antiviral therapy (ART) accumulatively, and 4445 of those were on treatment by the end of 2015.³ Among children living with HIV, the percentage of children less than 15 years old who are currently receiving ART is about 71.6%.⁴

In 2005, the national free pediatric ART program was launched by the Chinese Ministry of Health.⁵ China has made great progress in expanding the pediatric ART program since then.^6

–9 By 2016, from the initial six pilot provinces, the pediatric ART program had expanded to all 31 provinces and autonomous regions. However, challenges remain. One of these challenges is the specificity of ART in children. Childhood is the key phase for physical growth and development.¹⁰ An undisputed fact is that HIV, as a chronic progressive infectious diseases of humans, retards growth.¹¹

In the past several years, foreign researchers have done much research to figure out the trajectories of weight- and height-for-age Z-scores after receiving ART. However, the growth patterns after initiating ART were not completely consistent.^{11

–18} Some studies concluded that many of the deficits in growth due to HIV infection are reversed with ART, for the reason that these HIV-infected children exhibited consistent improvements in both weight- and height-for-age Z-scores after initiating ART.^14
–16 However, several studies failed to find improvements in height-for-age Z-score.^17,18

Many of these studies have been conducted in Africa, where levels of under nutrition and the pediatric ART program are different from China. Thus, we have conducted the retrospective observational cohort study to explore the trajectories of weight- and height-for-age Z-scores after ART, and to identify characteristics at ART initiation that influence growth trajectories in China.

Methods

Study subjects

Based on the National Major Scientific and Technological Project for Exploration and Application of Optimized Pediatric Antiretroviral Treatment during the Twelfth Five-year Plan Period, HIV-infected children who initiated ART in 2012 were enrolled for analysis. In China, treatment is recommended for all children who meet the criteria¹⁹ (Table 1).

Table 1.

Summary of Recommendations on When to Start ART in Children in China in 2012

Age	When to start
Infants (<1 year)	Treat all individuals
1 year to <5 years	Children ≤2 years or with WHO stage 3 or 4 or CD4 count ≤750 cells/mm³ or CD4 < 25%
5 years and above	WHO stage 3 or 4 or CD4 ≤ 350 cells/mm³ or <15%

ART, antiviral therapy.

Evaluating indicators

We used the Z-score method recommended by WHO as a reference standard to evaluate the nutritional status of children.²⁰ The Z-score includes WAZ (for children less than 10 years old) and HAZ. Children with WAZ < −2 and HAZ < −2 were defined as underweight and stunted, respectively. The extreme Z-scores are defined as follows: WAZ < −6 or WAZ > 5; HAZ < −6 or HAZ > 6. Children with these extreme Z-scores were excluded according to the definition by WHO Anthro.²¹ Severe immunodeficiency was defined by CD4% <15% or CD4 < 200/μL; moderate immunodeficiency, by CD4% = 15–25%, or CD4 = 200–349μL; and mild or no immunodeficiency, by CD4% > 25%, or CD4 ≥ 350/μL.

Study methodology

Baseline information of patients was collected when ART was initiated, and it included age, gender, immunodeficiency, WHO clinical stage, transmission mode, and initial treatment regime. The most common ART regimens used in this cohort are zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP)/efavirenz (EFV)/lopinavir with ritonavir (LPV/r) or abacavir (ABC) + lamivudine (3TC) + nevirapine (NVP)//efavirenz (EFV)//lopinavir with ritonavir (LPV/r).

The endpoint of our analysis was December 31st, 2014, or occurrence of the following events before the termination of the observation date: death, loss to follow-up, and transfer to adult care. WAZ and HAZ were observed at 0, 3, 6, 12, 18, and 24 months after ART initiation.

WAZ and HAZ were assessed from visit records every 3 months in the database. If a patient receives a follow-up within 60 days (∼2 months) or 3, 6, 12, 18, and 24 months after treatment initiation, she or he will be included for analyses for those endpoints. Using sensitivity analyses, we assessed the effects of using different time intervals to get the data of follow-up, especially weight and height, including 30, 45, and 75 days. Nutritional status in the last follow-up visit was compared with that at baseline, to figure out the proportion that recovered to normal and was retained in malnutrition.

Statistical analysis

Treatment outcomes were evaluated using linear mixed-effects models. As changes in WAZ seem like a polyline, we used two models to calculate Z-score before 6 months and after 6 months, respectively. In crude and adjusted models, we considered time on ART, gender, baseline CD4 cell count, immunodeficiency, age at ART initiation, and initial regime with or without LPV/r. Because the WHO clinical stage is defined by severe clinical manifestations, this variable was excluded from the analyses. Coefficients were calculated in these models. Coefficients >0 indicate that the variable is a protective factor of WAZ/HAZ improvements, whereas the coefficients <0 indicate that the variable is a risk factor. A p-value <0.05 was considered significant, and all analyses were performed using SAS version 9.3.

Results

Characteristics of the study population

From January 2012 to December 2012, 759 HIV-infected children started antiretroviral therapy. Four of them were older than 15 years and were excluded, and another nine children were excluded due to missing data during follow-up. There were 746 children who met the eligibility criteria. Of these, 380 (51.1%) participants were boys. Median age was 6.3 (4.0, 9.0) years; 712 (95.7%) children were infected from their mother; 319 (42.9%) had an initial CD4+ cell count exceeding 350 cells/μL; 234 (31.5%) had less than 200 cells/μL; and 50% (375) of them were in WHO stage I at ART initiation. Only 9.3% of the participants were using LPV/r-based regimen, whereas most of them were on an NNRTI-based regimen (Table 2).

Table 2.

Baseline Demographic and Behavioral Characteristics of HIV-Infected Children (N = 744) Who Initiated ART in 2012

Variables	N	%
Total	744
Gender
Male	380	51.08
Female	364	48.92
Age at ART initiation (year)
Median (IQR)	6.27 (3.95, 8.94)
0–5	286	38.44
6–10	327	43.95
11–15	131	17.61
Transmission mode
Mother to child	712	95.70
Others	32	4.30
Baseline CD4 cell count (cells/μL)
≥350	319	42.88
200–350	191	25.67
<200	234	31.45
WHO clinical stage
I	375	50.40
II	171	22.98
III	146	19.62
IV	52	6.99
Initial regime
With LPV/r	69	9.27
Without LPV/r	675	90.73
Underweight	125	21.37
Median WAZ (IQR)	−1.77 (−2.71, −0.67)
Stunted	301	42.28
Median HAZ (IQR)	−1.05 (−1.83, −0.25)

ART, antiviral therapy.

Weight-for-age Z-score after ART initiation

Five hundred eighty-five participants who were less than 10 years old had at least one follow-up datum. WAZ increased from −1.06 to −0.17 during the first 6 months after ART and then almost got stabilized. Mean Z-score increased from −1.06 to −0.60 at 24 months after the initiation of ART. Correspondingly, the proportion of underweight children decreased from 21.37% at ART initiation to 13.27% after 24 months on treatment (Fig. 1). Among the 125 (21.4%) underweight children at baseline, WAZ improved in 69 (11.8%) patients, regained −2 or more. However, 34 (5.8%) children with WAZ ≥ −2 were found to become underweight after treatment (Table 3).

FIG. 1.

Mean (95% CI) weight-for-age Z-scores by time since ART initiation in children with HIV/AIDS in China.

Table 3.

The Proportion of Malnutrition (HAZ and WAZ) After ART Compared with Baseline

	Baseline		Total
After ART	HAZ < −2	HAZ ≥ −2
HAZ < −2	178 (25.00%)	74 (10.39%)	252
HAZ ≥ −2	123 (17.28%)	337 (47.33%)	460
Total	301	411	712

	Baseline		Total
After ART	WAZ < −2	WAZ ≥ −2
WAZ < −2	56 (9.57%)	34 (5.81%)	90
WAZ ≥ −2	69 (11.79%)	426 (72.82%)	495
Total	125	460	585

ART, antiviral therapy.

In both crude and adjusted models, WAZ increased for 0.052 units during every additional month of ART in the first 6 months. After 6 months, WAZ was relatively stable. The adjusted model showed that female and baseline CD4 ≤ 200 cells/μL were negatively related to WAZ improvement in the first 6 months. After 6 months, female and older age at ART initiation (6–10 years old) were negative factors for WAZ improvement (Table 4).

Table 4.

Results of the Linear Mixed Models Analysis for WAZ and HAZ After ART Initiation

	Weight-for-age Z-score				Height-for-age Z-score
	0–6 months Coefficient (SE)	p	>6 months Coefficient (SE)	p	Coefficient (SE)	p
Crude model
Time (per month) on ART	0.052 (0.0070)	<0.0001	0.0041 (0.0043)	0.35	0.014 (0.0022)	<0.001
Adjusted model
Time (per month) on ART	0.052 (0.0073)	<0.0001	0.0038 (0.0043)	0.39	0.014 (0.0022)	<0.001
Gender
Male	1		1		1
Female	−0.21 (0.11)	0.043	−0.29 (0.11)	0.007	−0.057 (0.11)	0.61
Immunodeficiency
Mild or not	1				1
Moderate	−0.0052 (0.13)	0.97	0.051 (0.14)	0.72	−0.17 (0.15)	0.23
Severe	−0.40 (0.12)	0.0010	−0.063 (0.13)	0.62	−0.54 (0.14)	<0.001
Age at ART initiation (year)
0–5	1				1
6–10	−0.12 (0.11)	0.28	−0.41 (0.11)	0.0003	0.0036 (0.13)	0.98
11–15	—	—	—	—	−0.34 (0.17)	0.042
Initial regime
Without LPV/r	1		1		1
With LPV/r	0.32 (0.17)	0.063	0.29 (0.18)	0.12	0.21 (0.19)	0.28

ART, antiviral therapy.

Height-for-age Z-score after ART initiation

Seven hundred twelve participants have at least one follow-up height datum. HAZ increased steadily during the ART period. Mean Z-score increased from −1.71 to −1.30 at 24 months after the initiation of ART (p < 0.001). Correspondingly, the proportion of stunted children decreased from 42.3% at ART initiation to 33.7% at 24 months after ART (Fig. 2). Among the 301 (42.3%) stunted children at baseline, HAZ improved in 123 (17.3%) patients, regained −2 or more. However, 74 (10.4%) children with original HAZ ≥ −2 were found to become stunted after treatment (Table 3).

FIG. 2.

Mean (95% CI) height-for-age Z-scores by time since ART initiation in children with HIV/AIDS in China.

In both crude and adjusted mixed linear models, HAZ increased 0.014 units during every additional month of ART. The adjusted model showed that baseline CD4 ≤ 200 cells/μL and older age at ART initiation (11–15 years old) were negatively related to HAZ improvement in the first 6 months (Table 4).

Discussion

In this study, we found that both weight-for-age Z-score and height-for-age Z-score improved after the initiation of ART, just like previous studies in other countries.^11,22,23 The main difference occurs after 6 months after the initiation of ART.

The trajectories of WAZ in this study are different from those of HAZ; WAZ improved for the first 6 months and then stabilized, whereas HAZ consistently improved over time. In a study from Abidjan, Côte d'Ivoire, it was found that WAZ improved during treatment, whereas HAZ did not change significantly.¹⁸ They believed that with a longer period of observation, HAZ would also improve. Also in the studies of both Southern Africa²³ (between June 1, 1999 and February 29, 2008) and Zambia¹¹ (between September 30, 2007 and September 30, 2009), minimal improvements in WAZ were found after the first 6 months. The latter gave a possible explanation that half of their participants were underweight, and through stratified analysis they found that different from normal-weight children, their underweight counterparts are more likely to show little improvement after the first 6 months.¹¹ In our study, we did the same stratified analysis but failed to find similar results. Also, a study in South Africa claimed that the WAZ of underweight patients improved more, compared with normal children.¹⁵ In fact, after 24 months of treatment, only 13.3% of the participants were underweight and the median of WAZ was 0.60; whereas 33.7% of the participants were stunted as measured by HAZ. So it is understandable that the trajectories of WAZ in this study are different from those of HAZ. In addition, it is impossible for the Z-score to keep increasing. Instead, after increasing to a certain degree, it stays in a balanced and proper numerical range.

A relatively older age and lower baseline CD4 cell counts or percentage are associated with lower WAZ and HAZ. Several studies by us have got similar results.^11,24 Overall, 95.0% of the participants are infected due to mother-to-child transmission, which means that they have suffered from HIV since birth. Such a chronic wasting disease will retard the increase of both weight and height. Thus, the key to solve the problem is early diagnosis and treatment before CD4 cell counts or percentage drop too low and it becomes too late for children to start therapy. A randomized study from Southeast Asia also demonstrated the importance of early ART in HIV-infected children in terms of a variety of quality-of-life issues, including growth.²⁵

Compared with boys, girls were found to be related to lower WAZ. Though a study depicts the results that boys were 28% more likely to be underweight,²⁶ it also claimed that the reasons of this association between gender and malnutrition remain unclear and need further investigation.

There are limitations in this analysis. First, the study is based on observational data with inherent biases. Even though we adjusted many known factors, residual confounding may occur. For example, the database did not collect information on edema of children, breastfeeding, and orphan status. Edema is common in malnourished children, but it increases weight at the same time, leading to an underestimation of the prevalence of underweight.²⁷ Second, in the study, we found that a small proportion of HIV-infected children with HAZ or WAZ ≥2 at baseline may suffer from decreased HAZ or WAZ after treatment. We did not find significant reasons, which may due to very few cases and other social factors that were not collected in our database. Third, estimates of ART adherence were not available due to a lack of accurate methods. Unlike some other chronic illnesses, HIV-infected children may experience more difficulties in their daily lives, such as parental death from AIDS and stigmatization.^28,29 These stressful life events were associated with poor adherence.³⁰ Last, we could not do virological tests for all these children every 3 months because of the limited funds.

Results of the study show that the pediatric ART program in China effectively improves the nutritional status of HIV-infected children; more specifically, both weight-for-age Z-score and height-for-age Z-score were increased after ART. However, after 24 months on treatment, 13.27% and 33.67% were observed with regard to underweight and growth retardation, respectively. ART may not completely reverse malnutrition caused by HIV due to its complexity.¹⁷ However, early diagnosis and treatment, with an effective nutrition program led by the government, should be considered in the near future.

Footnotes

Acknowledgments

Funding sources: National Science and Technology Major Project of the Ministry of Science and Technology of China (2012ZX10001004) (2014ZX10001002).

Author Disclosure Statement

No conflicting financial interests exist.

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