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. 2020 May 29;10(3):259–266. doi: 10.1093/jpids/piaa054

Effect of the Timing of Antiretroviral Treatment Initiation on Outcomes in Children Living With Human Immunodeficiency Virus Admitted With Severe Acute Malnutrition

Moherndran Archary 1,2,✉, Benn Sartorius 3, Philip La Russa 4, Thobekile Sibaya 2, Micheal Healy 5, Raziya A Bobat 1,2
PMCID: PMC8023316  PMID: 32469406

Abstract

Background

Delays in early infant diagnosis and antiretroviral treatment (ART) initiation in developing countries frequently result in malnutrition at initial presentation with associated higher mortality and delayed immune recovery. The optimal timing of ART initiation is yet to be established.

Methods

Eighty-two children admitted with HIV and severe acute malnutrition (SAM) between July 2012 and December 2015 were enrolled. Patients were randomized to initiate ART within 14 days from admission (early arm) or delay ART initiation until nutritional recovery and >14 days after admission (delayed arm). All patients received a standardized treatment and feeding protocol and were followed to 48 weeks.

Results

The mean age of the patients at baseline was 23.3 months (standard deviation [SD], 27.9; range, 1.6–129 months). The mean time from admission to ART initiation was 5.6 days (SD, 4.4) in the early arm and 23 days (SD, 5.8) in the delayed arm (P < .001). There was no significant difference in mortality (P = .62), virologic response (P = .53), and anthropometric response (P = .57) between the 2 groups at 48 weeks. However, the rates of change in CD4, viral load, weight for age z score, and height for age z score occurred earlier and favored the delayed arm at early time points but were not significant at 24 and 48 months.

Conclusions

Despite initial improved responses in the delayed arm, lack of difference in outcome at 48 weeks supports a pragmatic approach with earlier ART initiation in children living with HIV admitted with SAM.

In this randomised controlled study of ART initiation in children admitted with HIV and severe acute malnutrition (SAM), despite initial improved responses in the delayed arm, lack of difference in outcome at 48 weeks supports a pragmatic approach with earlier ART initiation in children living with HIV admitted with SAM.

Clinical Trials Registration

PACTR 21609001751384.

Keywords: ART initiation, timing, severe acute malnutrition (SAM)

Despite an effective prevention of mother-to-child transmission program, approximately 160 000 children aged <15 years were living with human immunodeficiency virus (HIV) in South Africa in 2015 [1]. Ensuring early access to antiretroviral treatment (ART) is vitally important for improving outcomes of these children; however, only 54% of eligible children receive ART [1]. This large gap in ART access is likely due to delays in HIV diagnosis and ART initiation, resulting in children presenting with more advanced clinical presentations such as malnutrition. Malnutrition, therefore, remains a common clinical syndrome at initial presentation in children living with HIV from low- and middle-income countries (LMIC) [2].

Children living with HIV with severe acute malnutrition (SAM) represent a distinct clinical entity characterized by a complex interplay between increased energy expenditure with an increased basal metabolic rate, higher rates of coinfections, diarrhea and malabsorption, increased micronutrient deficiencies, and higher rates of food insecurity and poverty [3]. Management is complicated by gastrointestinal side effects to antiretroviral drugs, altered lipid and glucose metabolism, and altered pharmacokinetics of ART and antibiotics [4]. ART initiation in malnourished children is further complicated by physiological changes during nutritional recovery with potential effects on the frequency of adverse effects and pharmacokinetics [5, 6].

Despite nutritional rehabilitation, the CD4 counts in severely malnourished children living with HIV continue to decline, and they have a 3-fold higher probability of mortality compared with their noninfected counterparts [7, 8]. Although ART in children living with HIV has significantly improved survival and quality of life, SAM remained an independent predictor of mortality even with appropriate immunologic and virologic responses to ART [9–13].

In 2010, the World Health Organization’s (WHO) Nutrition Guideline Advisory Group identified determination of the optimal timing of ART initiation and ART dosing for children living with HIV with SAM as a key issue for which guidance must be developed [14, 15]. A more recent systematic review found a paucity of quality data in this area and found no randomized, controlled trials addressing the antiretroviral treatment of children living with HIV with SAM [16]. Therefore, we conducted a prospective, randomized, controlled trial to evaluate and compare the virologic, immunologic, and anthropometric responses of initiating ART before or after nutritional recovery in children living with HIV admitted with SAM.

METHODS

Patients were recruited from July 2012 through December 2015 from King Edward VIII Hospital, a referral hospital with a 100-bed pediatric unit in Durban, South Africa. All ART-naive children admitted with SAM were eligible for inclusion in the Malnutrition and Antiretroviral Timing in Children with HIV (MATCH) trial.

SAM was defined per the WHO definition [17] and HIV was diagnosed per the South African National HIV Treatment Guidelines [18]. All patients were managed per the standardized hospital policy based on the WHO Guidelines for the Inpatient Treatment of Severely Malnourished Children with standardized refeeding guidelines [17]. Medical management of patients was at the discretion of the treating clinician.

Patients were randomized to either initiate ART within 14 days from admission (early arm) or delay ART initiation (delayed arm) until nutritional recovery (as defined below) and more than 14 days after admission. Patients achieved nutritional recovery when they reached a weight for height z score (WHZ) of –2, achieved at least 15% weight gain, or demonstrated resolution of edema and return of their appetite at the discretion of the treating clinician and dietician based on the ability to complete the minimum calculated dietary intake. A predetermined computer-generated randomization table was used, with randomization blocks of 10 weighted to ensure equal numbers of patients with tuberculosis (TB) in each arm.

Antiretroviral regimen and doses were per the South African National ART treatment guidelines (2012–2015) as follows: either abacavir, lamivudine, and lopinavir/ritonavir (aged <3 years) or abacavir, lamivudine, and efavirenz (aged >3 years) [18]. Patients who required rifampicin and lopinavir/ritonavir had additional ritonavir prescribed per the weight band dosage table [18].

Patients were followed up at 4, 8, 12, 24, and 48 weeks following admission. Clinical assessment included a clinical examination for adverse effects and anthropometric evaluations (weight, height, mid-upper arm circumference [MUAC]). At each study visit, patients had HIV viral load (VL) and CD4 count measured and a safety blood draw. Virologic treatment response was defined as an HIV VL <1000 copies/mL at 48 weeks. Immunologic treatment response was defined as an improved CD4 count to WHO immune stage 1 and 2 [19]. Anthropometric treatment response was defined as body mass index for age z score (BMIZ) or WHZ score of greater than –1 below the mean. Patients were clinically assessed at each study visit for features of an immune reconstitution inflammatory syndrome (IRIS) event (as defined by the IRIS diagnostic criteria by French [20]) [21]. All laboratory results were graded using the Division of AIDS grading tables [22].

Written informed consent was obtained from the caregivers of all children enrolled in the MATCH study. The trial was approved by the University of KwaZulu-Natal and King Edward VIII Hospital Biomedical Research Ethics Committee.

The sample size was calculated using SAS version 9.2 to detect a difference in nutritional recovery between the 2 arms (mean difference of 0.5 z score in WHZ) to achieve a power of 80% and a significance of 5% [23]. Data were analyzed using Stata 13.0 (StataCorp, College Station, TX). Analyses were performed per intention-to-treat. Significant time point comparisons of categorical end points by trial arm were assessed using the Fisher exact test. A mixed-effects linear model was used to assess changes in continuous markers over time by trial arm. A random-effects logistic regression was used to assess dichotomous end points (eg, response) by trial arm. An adjusted P value of < .05 was considered statistically significant.

RESULTS

A total of 82 patients were enrolled in the study, 40 in the early arm and 42 in the delayed arm. At week 48, 27 patients (68%) in the early treatment arm completed follow-up (6 deaths, 7 lost to follow-up [LTFU]). In the delayed arm, 31 patients (74%) completed follow-up (8 deaths, 3 LTFU).

Caregivers of patients who defaulted the week 48 visit were contacted by telephone; we were able to confirm that 2 patients in each arm were alive, in care but relocated to another city. The difference in the number of patients LTFU in the delayed arm compared with the early arm was not significant (17.5% vs 7.1%, P = .19).

The average age of the patients at baseline was 23.3 months (standard deviation [SD], 27.9; range, 1.6–129 months) with a slight male preponderance (n = 47.58%). The majority (78%) of the patients had low CD4 counts (WHO immune stage 3 or 4), and 58% were classified as severely immunocompromised (WHO immune stage 4). Lopinavir/ritonavir–based ART was the most common regimen with 87.8% (n = 35) and 88% (n = 37) of patients on this regimen in the early and delayed arms, respectively.

Comparison of patient characteristics by treatment arm at baseline revealed no significant differences apart from time from admission to ART initiation (P < .001), that is, mean of 5.6 days (SD, 4.4) in the early arm and 23 days (SD, 5.8) in the delayed arm. (Table 1).

Table 1.

Patient Characteristics at Baseline

Characteristic Early ART Initiation, N (SD) Delayed ART Initiation, N (SD) P Value
Total number (82) 40 42 …
Age (months) 25.7 (1.7–129) 21.1 (1.6–99.7) .64
Gender (M:F) 60% (24):40% (16) 55% (23):45% (19) .52
CD4 Abs (mean) 805 (800) 952 (745) .59
CD4 % (mean) 16% (4.5) 18% (8)
ABC/3TC/EFV 12% (10) 12% (5) .35
ABC/3TC/LPV/rtv 88% (30) 88% (37)
Time to ART initiation (days) 5.6 (4.5) 23 (5.8) .0001
Tuberculosis at baseline 38% (16) 35.7% (15) .49
Weight for age z score (mean) –3.5 (1.2) –3.4 (1.6) .54
Weight for height z score (mean) –2.2 (1.6) –2.2 (2.2) .36
MUAC (mean) 11.4 (1.6) 11.7 (2.1) .66
Hemoglobin (admission) 8.9 (2.1) 8.8 (2.1) .37
Total protein (mean) 66 (17.7) 65 (16.6) .44
Albumin (mean) 22.5 (8.3) 23.8 (6.9) .66
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Abbreviation: 3TC, Lamivudine; ABC, Abacavir; ART, antiretroviral treatment; EFV, Efavirenz; LPV, Lopinavir; MUAC, Mid-upper arm circumference; rtv, ritonavir; SD, standard deviation.

Mortality

During the 48-week study period, 14 patients (17%) died, 6 (15%) in the early arm and 8 (19%) in the delayed arm. The difference in the mortality between the 2 arms was not statistically significant (P = .63). The mean time from enrollment to death was 74.4 days (SD, 59.9; range 12–252 days), 92.7 days in the early arm compared with 60.8 days in the delayed arm. No patient died before ART initiation. The majority (78.6%) of deaths occurred before 12 weeks, 67% and 87.5% in the early and delayed arms, respectively.

Adverse Effects/IRIS

A total of 23 IRIS events were documented in 21 (25%) patients (2 patients had both TB and bacille Calmette-Guérin [BCG] IRIS), 13 (56.5%) in the early arm and 10 (43.5%) in the delayed arm (P = .38). Five patients (21.7%) developed unmasking TB IRIS during the study period, 2 in the early arm and 3 in the delayed arm, while 7 patients (30.4%) developed BCG IRIS (all with local BCG scar ulceration with regional lymphadenitis), 4 in the early arm and 3 in the delayed arm. The remaining IRIS events were dermatological manifestations, 3 patients with seborrheic dermatitis, 3 patients with candida skin rashes, and 1 patient each with herpes stomatitis, planar warts, vulval warts, molluscum contagiosum, and tinea corpus. None of the IRIS events required discontinuation of ART or resulted in mortality.

Following discharge from the hospital after study entry, 14 patients required readmission to the hospital, 5 (12.5%) in the early arm and 9 (21.4%) in the delayed arm. The majority (64%) of readmissions were due to lower respiratory tract infections, followed by acute gastroenteritis (21%). Sixty-four percent of readmissions occurred within the first 12 weeks following study entry.

None of the patients required alteration or discontinuation of ART due to a graded laboratory abnormality.

CD4 Count

At 48 weeks, 58.5% of patients were WHO immune stage 1, 19.5% were stage 2, 12.2% were stage 3, and 9.8% were stage 4 compared with 16%, 10.7%, 28.6%, and 44.6% at baseline.

There was a significant increase in the overall mean CD4 count from a baseline count of 878.5 cells/µL (SD, 772.8) to 1447.9 cells/µL (SD, 739.0) at 48 weeks (P  = .001). The mean CD4 count at week 48 was 1366.7 (SD, 732.4) cells/µL in the early arm and 1518.2 (749.8) cells/µL in the delayed arm (P = .53).

Comparison of the change in CD4 count using a multiple mixed-effects linear regression model (Figure 1) suggested no statistically significant difference in immune recovery between the 2 groups. However, the delayed arm did have a higher mean CD4 (more rapid gain) by week 12 compared with the early arm, with this difference narrowing toward 48 weeks. This difference at 12 and 24 weeks was not statistically significant (P = .43 and .44, respectively).

Figure 1.

Figure 1.

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(A) Mean CD4, (B) mean log VL, (C) delta mean CD4, and (D) delta mean VL from baseline by trial arm and time point. Abbreviations: VL, viral load.

Viral Load

At 24 weeks, 67.3% of combined patients achieved protocol-defined response (VL <1000 copies/mL) overall, 59.7% in the early arm compared with 75% in the delayed arm, but this difference was not statistically significant. By 48 weeks, the number of patients with protocol-defined virologic response increased to 81.1% overall [11], 77.8% [6] in the early arm and 84% [5] in the delayed arm. This difference at 48 weeks was not statistically significant before and after multivariable adjustment (odds ratio [OR], 1.66; P = .53; 95% confidence interval [CI], .34 to 8.06; Table 2).

Table 2.

Comparison of Primary Endpoints at 48 Weeks and Anthropometric Change From Baseline With 48 Weeks by Trial Arm

End Point Variable Odds Ratioa 95% Confidence Interval P Value
Anthropometric response at 48 weeks Late vs early (ref) 1.66 .29–9.31 .566
Virologic response at 24 weeks Late vs early (ref) 2.04 .52–7.98 .305
Virologic response at 48 weeks Late vs early (ref) 1.66 .34–8.06 .527
Mortality at 48 weeks Late vs early (ref) 1.38 .38–4.96 .621
Favorable outcomes at 48 weeks Late vs early (ref) 1.42 .49–4.12 .52
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aAdjusted for age, gender, World Health Organization immune stage at baseline, tuberculosis, hemoglobin at baseline, total protein at baseline, and albumin at baseline.

Using a stricter definition of virologic response (VL <400 copies/mL), 77.9% of patients achieved a virologic response at 48 weeks, 83.9% in the delayed arm and 70.37% in the early arm, again this difference was not statistically significant (OR, 2.02; P = .23; 95% CI, .64 to 6.36).

A multiple mixed-effects linear regression model to evaluate the VL end point and change therein at weeks 4, 8, 12, 24, and 48 showed an appropriate delay in VL reduction in the delayed arm compared with the early arm at week 4 (+1.57 mean log VL in the delayed arm, P < .001) and 8 (+0.79 mean log VL in the delayed arm, P = .09). At week 12, the log VL fall was equivalent (+0.22 mean log VL in the delayed arm; P = .63; 95% CI, –.66 to 1.1) in both arms. However, by week 24, the delayed arm had a statistically significant higher drop in log VL compared with the early arm (–1.06 mean log VL in the delayed arm; P = .02; 95% CI, –1.94 to –.18). This difference persisted to week 48 and remained statistically significant (–0.99 mean log VL in the delayed arm; P = .03; CI, –1.85 to –.12).

Anthropometry

At week 48, 76.6% of patients achieved an adequate anthropometric response, with similar responses in both arms (77.2% in the early arm and 76.6% in the delayed arm; P = .92). The adjusted comparison of anthropometric response at week 48 was not significant (OR, 1.66; P = .57; 95% CI, .29 to 9.31).

There were no significant differences in BMIZ or WHZ scores between the 2 arms at 48 weeks (OR, 0.79; P = .43; 95% CI, –.96 to 2.25). At week 48, the difference in weight for age z score (WAZ) between the 2 arms was marginally significant (OR, 1.67; P = .09; 95% CI, .11 to 1.44), while the difference in height for age z score (HAZ) was statistically significant (OR, 2.51; P = .01; 95% CI, .27 to 2.25; Figure 2). After adjusting for age, gender, immune stage, tuberculosis, hemoglobin, total protein, and albumin, only the change in HAZ remained marginally significant.

Figure 2.

Figure 2.

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(A) Mean BMIZ, (B) mean HAZ, (C) mean WAZ, and (D) mean WHZ by trial arm and time point. Abbreviations: BMIZ, body mass index for age z score; HAZ, height for age z score; WAZ, weight for age z score; WHZ, weight for height z score.

DISCUSSION

This prospective, randomized, controlled trial comparing early vs delayed ART initiation in a cohort of children living with HIV admitted with SAM demonstrated no significant differences in immunologic, virologic, or anthropometric treatment responses at 48 weeks despite significantly improved rates of change in the VL, WAZ, and HAZ, favoring the delayed arm at 24 weeks.

Since 2016, the WHO consolidated ART guidelines have, recommended that all children initiate ART on diagnosis irrespective of WHO clinical stage or CD4 count [24]. The question of the optimal timing of ART initiation in malnourished children has, to date, not been addressed in a randomized, controlled trial. The difference in the timing of ART initiation in this study was much earlier than previously reported for both arms (5.6 vs 23 days). In a Malawian retrospective, observational study of children with uncomplicated malnutrition receiving outpatient therapeutic feeding, ART initiation within 21 days had a higher rate of nutritional recovery (86% vs 60%, P < .01) and a higher rate of weight gain (3.6 vs 1.6 g/kg/day) when compared with those who initiated ART later [25]. In contrast, in an unpublished retrospective analysis of 345 Ugandan children living with HIV, where 21% of the cohort were moderate or severely malnourished, mortality in children who initiated ART within 10 weeks of diagnosis was higher compared with those who started ART later after adjustment for age, sex, CD4%, and WHO clinical stage (OR, 2.8; 95% CI, 0.33 to 5.9; P = .007) [16]. A randomized, controlled trial comparing urgent vs post-stabilization ART initiation in hospitalized Kenyan children (32% were malnourished) showed no difference in mortality at 24 weeks [26]. No previous study reported on the timing of the introduction of ART, in particular, at less than 14 days during nutritional rehabilitation for SAM [27].

In a systematic review of mortality associated with SAM in sub-Saharan Africa, children living with HIV had significantly higher mortality compared with children not living with HIV (30.4% vs 8.4%) during rehabilitation [2]. Few studies have reported specifically on mortality in children living with HIV with SAM beyond the rehabilitation phase [28]. In the MATCH cohort, the mortality at 48 weeks and the inpatient mortality rate were far lower than the reported mortality. The inpatient mortality was in line with the expected mortality in a well-resourced tertiary hospital, where patients were managed in a high-care setting. No significant difference in mortality and LTFU (which may represent unknown deaths) was demonstrated between the 2 treatment arms, although the study was not powered to detect differences in mortality. The majority of the mortality (78.6%) and hospitalizations (64%) occurred in the first 3 months following study entry, which is similar to other studies. Potential strategies to decrease these events, such as more frequent clinical assessments, education of caregivers of danger signs, and the need for urgent review at a healthcare facility and opportunistic infection prophylaxis, may be of benefit. In the REALITY trial, severely immune-compromised adult patients living with HIV who initiated ART with a regimen of enhanced opportunistic infection (OI) prophylaxis compared with standard prophylaxis demonstrated decreased mortality, new TB, cryptococcal or candida infections, and hospitalizations [29]. Additional studies to evaluate enhanced OI prophylaxis should be considered in children living with HIV with SAM and other high-risk criteria at ART initiation.

IRIS is a common clinical entity in children who initiate ART in LMICs, with a prevalence in the literature ranging from 20% to 38%, which is similar to the incidence reported in this study [21, 30]. TB IRIS was the most frequent presentation in a study of children living with HIV in Uganda (29%). Time on ART and pre-ART CD4 count were significantly associated with IRIS events; however, malnutrition (WHZ more than 2 SD) was not associated with an increased incidence of IRIS in the same study [31]. The absence of a significant difference in the frequency of TB IRIS between the arms could be due to the high proportion (36.9%) of patients who were initiated on TB treatment. In the current study, BCG IRIS was the most frequent IRIS event, which was not reported in the studies of Ugandan and Thai children. However, several case reports of BCG IRIS have been reported in South African children initiating ART [30, 32–34]. The presence of a high incidence of BCG IRIS may be related to the timing of vaccination and strain of BCG used in South Africa.

Once initiated on ART, maintaining patients in care is vitally important to achieving the WHO goal of 90% virologic suppression in patients initiated on ART [35]. In this study, all patients received the same package of counseling sessions, 1 post-test counseling session, and 3 adherence counseling sessions [36], and counsellors were unaware of the randomization of the patients. Patients in the early arm were started on ART before the counseling sessions were complete. The psychological impact of a caregiver being informed of a child’s HIV status concurrently with being counseled regarding the need to administer ART in the early arm may account for the difference in numbers of LTFU and the lower virological suppression seen at 24 weeks. Caregivers may require time to first assimilate and accept the diagnosis of HIV before being able to understand and accept the adherence to counseling sessions fully.

Data on virologic responses in children with SAM are limited due to limited access to routine VL testing in settings where SAM is common. Several studies have reported on virologic responses in sub-Saharan Africa and included malnourished children. In the PROMOTE trial, virologic response (VL <400 copies/mL) at 48 weeks was 80% and 76% for a lopinavir/ritonavir–based regimen and efavirenz-based regimens, respectively [37]. Although the difference in virologic response did not reach statistical significance in our study, the multiple mixed-effects linear regression model to explore changes in VL revealed a significant difference favoring the delayed arm at weeks 24 and 48. The model did confirm the delay in VL decline in the delayed arm at week 4 due to the delay in ART initiation. Altered pharmacokinetics of antiretroviral drugs in patients who initiated ART during the acute phase of nutritional recovery may account for the differences in the VL change, significantly favoring the delayed arm at weeks 24 and 48. A population pharmacokinetic study conducted during this study identified altered pharmacokinetic parameters for abacavir, lamivudine, and lopinavir/ritonavir in this population; however, these changes were not associated with treatment response at 48 weeks [38, 39].

Several studies from sub-Saharan Africa have documented good immunologic and growth responses in children living with HIV who are initiated on ART. Although the difference in immunologic and growth recovery between the arms was not statistically significant in our study, the increase in the CD4 count and WAZ and HAZ scores occurred earlier in the delayed arm. Delaying ART initiation may allow the gut microbiota time to normalize, decreasing microbial translocation and immune activation, thus facilitating more rapid immune recovery [40, 41]. Early ART initiation during nutritional recovery when there is increased gut permeability and gut microbiota dysbiosis may account for the delay in the rate of immunologic and growth responses seen in the first 24 weeks. Additional studies are required to explore this finding and develop potential adjunctive treatment strategies to improve immune recovery and growth.

CONCLUSIONS

Children living with HIV admitted with SAM and initiated on ART demonstrated significant improvements in CD4 counts and anthropometric parameters, together with significant VL reduction compared with baseline. In this randomized, controlled trial comparing early vs delayed ART initiation in children living with HIV admitted with SAM, the differences in CD4 count, viral suppression, and anthropometric response at 48 weeks were not significant, with no significant difference in the frequency of IRIS between the 2 groups. Based on the results of this study, we recommend a pragmatic approach with earlier ART initiation in children with SAM than previously studied, from the second week of admission and when the patient is clinically stable.

Notes

Acknowledgments. We thank the Malnutrition and Antiretroviral Timing in Children with HIV Study Team (Thobekile Sibaya, Micheal Healy, Alejandro Palma, Edem Binka, Diana Cristina, and Leora Sewnarain) and the parents and patients for participation in the study

Author contributions. M. A. was responsible for all aspects from concept development to manuscript writing. B. S. was responsible for analysis. P. L. R. was responsible for writing. T. S. and M. H. were responsible for data collection. R. A. B. was responsible for the concept and writing.

Financial support. This publication was made possible by grant R24TW008863 from the Office of the US Global AIDS Coordinator and the US Department of Health and Human Services, National Institutes of Health (NIH, Office of AIDS Research [OAR] and NIH Office of Research on Women’s Health [ORWH]).

Disclaimer. The contents presented here are solely the responsibility of the authors and do not necessarily represent the official views of the government.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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