In 2012, an estimated 530,000 tuberculosis (TB) cases and 74,000 TB deaths occurred in children <15 years.1 TB is common in HIV-infected children, with HIV prevalence among children with active TB ranging from 10% to 62%.2,3 In 2010, the World Health Organization (WHO) recommended initiation of combination antiretroviral therapy (cART) as soon as TB therapy is tolerated in HIV/TB coinfected children.4 Consequently, many children initiate cART while receiving TB treatment. Co-treated individuals may experience a differential response to cART because of drug–drug interactions,2,5 increased risk of drug toxicity,2,5 immune reconstitution inflammatory syndrome (IRIS),6 and potentially lower adherence because of the large amount of medications.5 In particular, interactions between protease inhibitors (PIs) and rifampicin can result in subtherapeutic plasma concentrations of both types of drugs,7 causing the need for increased PI dosing in children to achieve the desired virologic and immunologic outcomes.
In adults, receiving TB treatment at the time of cART initiation does not impair virologic or immunologic response to cART,8 though it may be associated with an increased risk of long-term mortality.9 Results of limited pediatric research to date suggest that starting cART during TB treatment improves survival10–12 and that concomitant TB treatment and cART do not increase mortality.13–15 The few studies that assessed the effect of TB treatment on virologic or CD4 cell response to pediatric cART observed lower rates of virologic suppression in children receiving TB treatment, especially in those receiving PI-based cART other than super-boosted lopinavir/ritonavir (LPV/r),15–17 but similar CD4 reconstitution14,15,17,18 and proportion with severe immunodeficiency during cART.19
We aimed to evaluate the impact of receiving TB treatment at the time of cART initiation on short- and long-term virologic and immunologic response to cART among a cohort of young children.
We performed a secondary analysis of data from the TB, HIV, IRIS, and Nutrition in Kids (THINK) study. This study prospectively followed (1) children receiving TB treatment who became eligible for cART and (2) children who were TB free at the time of cART initiation. The primary objectives of the parent study were to determine the incidence, timing, and clinical manifestations of TB–IRIS and Bacillus Calmette–Guérin–IRIS among children initiating cART, along with the association between malnutrition and the risk of developing TB–IRIS and Bacillus Calmette–Guérin–IRIS.
cART-naive children aged 0–8 years presenting between September 2009 and March 2012 at the Harriet Shezi outpatient pediatric HIV clinic or the Pediatric Wards of Chris Hani Baragwanath Hospital in Soweto, South Africa, who were eligible for cART were offered study participation. Children were followed up for 24 months or until August 2013. Children with at least one documented HIV RNA and/or CD4 cell percent (CD4%) result after cART initiation were included in this secondary analysis.
The study included a pre-cART visit, cART initiation visit, and visits every 3 months thereafter (±1 month) for 24 months. As part of routine care, caregivers of children who missed a scheduled visit were contacted to remind them of their missed appointment and encourage their return. Children who were transferred to a primary care facility were encouraged to return for the final 24-month visit. Patients who did not complete the 24-month visit were considered lost to follow-up and censored at the date of their last HIV RNA and/or CD4% measurement. Three patients were late for their 24-month visit and had laboratory measurements taken at 25.2, 26.0, and 26.6 months after cART initiation; these values were retained in analyses.
CD4% (LSRII flow cytometer; BD Biosciences, San Jose, California) and HIV RNA (Ultrasensitive Amplicor HIV Monitor assay; Roche Diagnostic Systems, Basel, Switzerland, lower limit of detection 50 copies/mL) were measured at or before cART initiation and during follow-up visits. Baseline values were those measured at cART initiation or the closest value within 4 months before initiation. Immunodeficiency and anemia were defined according to WHO age-specific classifications.20,21 Severe immunodeficiency was defined as CD4% <25% in children <11 months, <20% in children 12–35 months, <15% in children 36–59 months, and CD4 cell count <200 cells per microliter or CD4% <15% in children >5 years.20 Weight-for-age z scores were calculated using WHO Anthro (version 3.2.2) SAS macro22 for children <5 years and WHO AnthroPlus SAS macro23 for children 5–8 years.
Virologic suppression was defined as the first documented HIV RNA <50 copies per milliliter after cART initiation, whether or not confirmed by a subsequent measurement. Virologic rebound was defined as HIV RNA >1000 copies per milliliter after a prior measurement of <50. The primary measure of immunologic response was median increase in CD4% from baseline to 3, 6, 12, and 24 months of cART.
TB and HIV Clinical Care
Children were diagnosed and treated for TB24,25 and HIV26,27 according to South African guidelines. TB diagnosis was made based on a combination of clinical signs, contact with an adult with active TB, positive tuberculin skin test, suggestive chest x-ray, or positive sputum smear microscopy or culture.24 The National Health Laboratory Service processed all sputum samples. Starting in July 2011, a sputum sample was also evaluated by Xpert MTB/RIF. All children diagnosed with active TB were treated and generally received isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months followed by isoniazid and rifampicin for 4 months.
Before April 2010 in South Africa, children were eligible for cART if they had recurrent or prolonged HIV-related hospitalizations, WHO stage II/III disease,20 CD4% <20% (if ≤18 months), or CD4% <15% (if >18 months).27 Children ≤3 years or ≤10 kg initiated LPV/r-based cART (stavudine/lamivudine/LPV/r), and children >3 years and >10 kg initiated efavirenz-based cART (stavudine/lamivudine/efavirenz). Initiation of cART was delayed for at least 2 months in children receiving TB treatment, and children concomitantly on LPV/r-based cART and TB treatment received ritonavir at a 1:1 dosage with lopinavir (super-boosted LPV/r).
In April 2010, the South African guidelines changed. All children ≤1 year were eligible for cART on HIV diagnosis.26 Children 1–5 years were eligible for cART if WHO stage III/IV, CD4% ≤25%, or CD4 count <750 cells per microliter. Children >5 years were eligible if WHO stage III/IV or CD4 count <350 cells per microliter. Children ≥3 years and ≥10 kg initiated efavirenz-based cART (abacavir/lamivudine/efavirenz), and LPV/r-based cART (abacavir/lamivudine/LPV/r) was used for children <3 years or <10 kg. Initiation of cART was recommended to be delayed for 2–4 weeks after starting TB treatment, and children concurrently on TB treatment and LPV/r-based cART received added ritonavir, either super-boosted LPV/r for younger children or double-dose LPV/r for older children.26 The updated guidelines also recommended decentralization of cART initiation and follow-up to primary care clinics.
Wilcoxon rank sum tests were used to compare continuous demographic and clinical variables between groups, Pearson χ2 test was used for categorical variables, and exact P values were calculated when appropriate.
To examine virologic suppression, the median time to suppression was calculated. Distributions of event times in each exposure group were examined using the Kaplan–Meier function and compared by the log rank test. Crude and multivariable Cox proportional hazard regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Time of origin was the date of cART initiation; patients were censored at the earliest occurrence of death, loss to follow-up, or 24-month visit. Covariates included cART guidelines (pre-2010 vs. 2010 guidelines), age (<2.1 vs. ≥2.1 years), sex, weight-for-age z score (less than −3 vs. −3 or higher), baseline HIV RNA (<5.5 vs. ≥5.5 log10 copies/mL), baseline CD4% (continuous), cART regimen (efavirenz based vs. LPV/r based), and baseline hemoglobin (continuous). Similar methods were used to assess virologic rebound, limiting the analysis to patients who ever experienced virologic suppression.
Median CD4% increases were calculated, both overall and stratified by TB treatment status, and were compared using Wilcoxon rank sum tests. The proportion of children with severe age-specific immunodeficiency20 at each visit was also examined.
In addition to the main analysis, we performed exploratory sensitivity analyses stratified by (1) cART regimen and (2) timing of cART initiation relative to the 2010 change in guidelines. As new guidelines were implemented over several months, children who initiated cART from April to October 2010 were classified as initiating care according to the pre-2010 guidelines if their initial regimen included stavudine or as initiating according to the 2010 guidelines if their initial regimen contained abacavir. An additional sensitivity analysis examined an alternative virologic suppression definition of HIV RNA <400 copies per milliliter.
Study data were collected and managed using Research Electronic Data Capture (REDCap)28 hosted at the University of North Carolina—Chapel Hill. All analyses were performed using SAS (version 9.3, SAS Institute, Cary, NC).
Children were enrolled after parental permission and child assent procedures (for children ≥7 years). Institutional Review Boards of the University of North Carolina at Chapel Hill and University of Witwatersrand approved the study.
Of the 246 children enrolled in the THINK study who initiated cART, 199 had ≥1 follow-up HIV RNA and/or CD4%. Children included in analyses were representative of all 246 children who initiated cART (for a comparison of children included vs. not included in analyses, see Table, Supplemental Digital Content 1,http://links.lww.com/QAI/A552), except for lower baseline HIV RNA and CD4% and a greater proportion on LPV/r-based cART.
At cART initiation, 92 (46%) children were receiving TB treatment and 107 (54%) were not receiving TB treatment (Table 1). Median age was 2.1 years [interquartile range (IQR) 0.9–4.6], 52% were males, 12% presented with severe undernutrition (weight-for-age z score less than −3), and 52% had moderate or severe anemia. Median baseline CD4% was 17.1 (IQR 11.6–23.3); 108 (57%) had severe immunodeficiency at cART initiation. Median baseline HIV RNA was 5.6 log10 copies per milliliter (IQR 4.9–6.0). Two-thirds (66%) initiated cART according to 2010 guidelines. Sixty percent initiated an LPV/r-based first-line cART regimen; the remaining 40% received efavirenz-based cART. Children on LPV/r-based cART were younger and more likely to have severe undernutrition, lower baseline hemoglobin, higher baseline HIV RNA, higher baseline CD4%, and more severe age-specific immunodeficiency than children initiating efavirenz-based cART (for a comparison of children initiating LPV/r-based vs. efavirenz-based cART, see Table, Supplemental Digital Content 2,http://links.lww.com/QAI/A552).
Median duration of TB treatment at time of cART initiation was 23 days (IQR 15–39, range 0–180) (Table 1). Consequently, most children receiving co-treatment did so for ≥5 months. Children receiving TB treatment were more likely to be males (60% vs. 45%, P = 0.04), were slightly older, and had lower baseline hemoglobin (9.6 vs. 10.3 g/dL, P = 0.01), weight-for-age z scores (−1.81 vs. −1.29, P = 0.02), and median CD4% (15.3% vs. 18.8%, P < 0.01) than children not on TB treatment. Baseline median HIV RNA was similar among those receiving and not receiving TB treatment (5.4 vs. 5.6 log10 copies/mL, P = 0.3).
Duration of follow-up ranged from 2.2 to 26.6 months (median 23.8, IQR 20.6–24.1) and did not differ by TB treatment status (P = 0.6, Table 1). Sixty (30%) children did not complete the 24-month follow-up visit and were censored at their date of last visit. Of these, 29 (48%) were receiving TB treatment at cART initiation and 22 (37%) did not have 24 months of follow-up before the study stopped in August 2013. During follow-up, 24 (12%) children switched cART: 7 from efavirenz-based to LPV/r-based cART, 1 from LPV/r-based to efavirenz-based cART, 12 within LPV/r-based cART, and 4 within efavirenz-based regimens. TB treatment was not associated with regimen switching (15% vs. 9%, P = 0.2). Only one death was documented during follow-up; the child was not receiving co-treatment of TB and died at 2.3 years of age, 23 months after cART initiation.
The number of children with available viral loads at each visit is described in Supplemental Digital Content 3 (see Table,http://links.lww.com/QAI/A552). Time to virologic suppression ranged from 0.5 to 25.2 months, with a median of 6.2 months among both children receiving and not receiving TB treatment (Table 2), with consistently overlapping Kaplan–Meier curves in the 2 groups (log rank P = 0.7, Fig. 1A). TB treatment also did not significantly affect the hazard of virologic suppression [adjusted HR (aHR) 1.36, 95% CI: 0.94 to 1.96, Table 2]. By 12 months after cART initiation, 124 (62%) children experienced virologic suppression <50 copies per milliliter and had not yet rebounded >1000 copies per milliliter (63% vs. 62% in children receiving vs. not receiving TB treatment).
Using an alternative suppression definition of <400 copies per milliliter resulted in decreased time to suppression (from a median of 6.2 to 5.7 months), increased proportion suppressed by 12 months (from 62% to 74%), and decreased time to rebound (from 18.3 to 17.5 months) but did not change the proportion that rebounded or any HRs of interest (for analyses using a suppression definition of <400 copies per milliliter, see Tables, Supplemental Digital Content 4–6,http://links.lww.com/QAI/A552).
Overall, 164 (82%) patients had experienced virologic suppression and were included in the virologic rebound analyses (Table 2). Similar proportions of patients receiving and not receiving TB treatment experienced virologic rebound (23% vs. 24%, P = 0.9), with substantial overlap between the Kaplan–Meier curves (log rank P = 0.8, Fig. 1B). Time to virologic rebound ranged from 6.8 to 26.0 months from cART initiation. TB treatment did not affect time to virologic rebound (18.3 vs. 17.8 months, P = 0.9) or hazard of virologic rebound over 24 months after cART initiation (aHR 1.53, 95% CI: 0.71 to 3.30).
Children on TB treatment had lower CD4% in the first 12 months of cART, after which they caught up to children not on TB treatment (Table 2, Fig. 2A). Children receiving and not receiving TB treatment at cART initiation had a similar median CD4% increase at 3 months (7.2% vs. 6.5%), 6 months (9.9% vs. 9.6%), 12 months (14.2% vs. 11.9%), and 24 months (14.5% vs. 14.2%) (all P ≥ 0.06, Table 2), but a higher proportion of children on TB treatment had severe age-specific immunodeficiency throughout follow-up (Fig. 2B).
Exploratory Analysis by cART Regimen
cART regimen had a greater effect on virologic suppression than TB treatment, with children on efavirenz-based regimens experiencing shorter median time to suppression (5.5 vs. 7.7 months, P < 0.01) as compared with children on LPV/r-based cART (for a cART regimen–stratified Kaplan–Meier suppression graph, see Table, Supplemental Digital Content 7,http://links.lww.com/QAI/A552). cART regimen did not seem to influence virologic rebound (aHR 0.62, 95% CI: 0.15 to 2.52) or CD4% reconstitution.
Among children on LPV/r-based regimens, children on TB treatment tended to have similar virologic suppression (aHR 1.04, 95% CI: 0.64 to 1.69), increased virologic rebound (29% vs. 20%, P = 0.3), and higher hazard of rebound (aHR, 2.34, 95% CI: 0.80 to 6.83), had significantly lower CD4% at 3, 6, and 12 months, and had higher proportions with severe immunodeficiency at 6, 12, and 24 months compared with children on LPV/r not receiving TB treatment (Table 3). In contrast, among children on efavirenz-based cART, no significant effect of TB treatment was observed, with similar hazard of virologic suppression (aHR 1.66, 95% CI: 0.88 to 3.16), similar hazard of virologic rebound (aHR 1.03, 95% CI: 0.26 to 4.12), and no significant differences in immunologic response between children on efavirenz-based cART who did and did not receive TB co-treatment.
Exploratory Analysis by Timing of cART Initiation
Children initiating cART according to pre-2010 guidelines had a shorter median time to suppression (5.7 vs. 6.5 months, P = 0.01) and greater hazard of suppression over time (aHR 1.94, 95% CI: 1.35 to 2.80) compared with those initiating cART according to 2010 guidelines (for analyses stratified by timing of cART initiation, see Table, Supplemental Digital Content 8,http://links.lww.com/QAI/A552). They also consistently experienced lower CD4% increases and higher proportions of severe immunodeficiency, though the differences were not statistically significant.
Children receiving TB treatment at cART initiation did not have a substantially different response to cART, with similar rates of virologic suppression, virologic rebound, and CD4% increase. Children initiating cART while on TB treatment presented with more advanced disease at baseline and remained more vulnerable as they continued to have lower CD4% and a higher prevalence of severe immunodeficiency throughout the first 2 years of cART. Similar to observed responses in adults,29 efavirenz-based cART was superior to LPV/r-based cART, with more and quicker suppression compared with LPV/r-based regimens. In young children, our exploratory sensitivity analysis indicates that the combination of TB treatment and super-boosted LPV/r-based cART may increase the risk of rebound and diminish CD4% reconstitution, a finding in accordance with prior studies15,17 and with known drug–drug interactions between PIs and rifampicin, which can result in subtherapeutic plasma concentrations of both types of medications.7
We did not observe an effect of TB treatment on virologic suppression, a key measure of successful cART,2 among children on nonnucleoside reverse transcriptase inhibitor–based cART, a finding similar to that reported by Zanoni et al. Three studies have reported decreased virologic suppression rates in young children receiving concurrent PI-based cART and TB treatment. Zanoni et al16 found that children <3 years on super-boosted or double-dosed PI-based cART and concomitant TB treatment experienced decreased suppression compared with children not receiving TB treatment. Frohoff et al15 also observed that TB treatment decreased suppression among young children <2 years on double-dose LPV/r and ritonavir-based cART, and Reitz et al17 found decreased suppression by 39 weeks among children <2 years on ritonavir or unboosted LPV/r-based cART being co-treated for TB.17 Among children on LPV/r-based cART receiving concurrent TB treatment at cART initiation, we did not observe a decrease in virologic suppression. However, our median observed time to virologic suppression was 6.2 months, which was longer than the 13–14 weeks reported by Reitz et al17 and may be partially attributed to infrequent sampling for viral load in our cohort. The sparse viral load data, especially at the 3-month visit when there is overlapping administration of TB and cART medications, may have masked a true difference in virologic suppression rates. Even though we did not observe differences in suppression rates, we did observe an increased hazard of virologic rebound in children receiving LPV/r-based cART and TB treatment, supporting the potential for an inferior virologic response in children receiving LPV/r-based cART together with TB treatment in the first months of cART.
Virologic rebound may indicate an unsuccessful cART regimen, inadequate adherence, or the emergence of drug-resistant virus and is an especially important indicator in children because of the limited treatment options.2 We did not find TB treatment to affect virologic rebound overall, though there was a clinically meaningful increase in virologic rebound among children <3 years on LPV/r-based cART. Reitz et al17 found a lower incidence of rebound among children on PI-based cART and TB treatment within 16 weeks after suppression (2.8% vs. 12%), whereas we found no significant difference at this time point (4.8% vs. 2.0%, P = 0.6).
Immune reconstitution is crucial, as a longer time spent at low CD4% is associated with increased risk of morbidity and mortality.2 We found children receiving TB treatment to have lower CD4% in the short term, but no impairment of median CD4% increase. This finding is in accordance with previous studies14,15,17,18 and extends this observation to 24 months of cART.
This study possessed a number of important strengths. The THINK study was prospective, enabling us to firmly establish the timing between TB treatment and cART initiation and to obtain regular HIV RNA and CD4% measurements during follow-up. Children were followed up for 2 years, allowing us to distinguish between short- and long-term effects of TB treatment. The occurrence of only one documented death allowed us to study response to cART without survival bias. Most children were very young (median age 2.1 years), an age group which tends to be underrepresented in cART programs and research studies but is becoming larger with increasing access to early infant diagnosis.19
This study was, however, not without limitations. The observational design nested within routine care resulted in loss to follow-up, missing data, and required adaptations to changing guidelines over time. Classification of virologic rebound using a single HIV RNA measurement >1000 copies per milliliter may have included blips. Adherence data for TB treatment and cART were not available and most TB diagnoses were presumptive, resulting in potential misclassification of active TB. However, given our primary exposure was administration of TB treatment at cART initiation, exposure misclassification is likely less of a concern and results are applicable to all children on TB treatment at cART initiation. Although TB treatment duration before cART initiation may affect response to cART, we could not assess this because of limited variability in time lag between start of TB treatment and cART initiation (median 23 days, IQR 15–39). Finally, as cART regimen was prescribed according to age and weight, it was difficult to separate the individual effects of these exposures.
In conclusion, despite a multitude of challenges posed by concomitant TB and HIV treatment in young children,30,31 our findings indicate that children ≥3 years on efavirenz-based cART and TB treatment do not experience an inferior cART response. This is similar to the situation in adults8 and reinforces WHO recommendations to initiate cART soon after TB treatment is tolerated.4 In young children, our exploratory sensitivity analyses suggest that the combination of TB treatment and super-boosted LPV/r-based cART may increase the risk of rebound and diminish CD4% reconstitution. As guidelines and treatment options evolve, further research is needed to determine optimal HIV/TB co-treatment regimens, especially for children aged <3 years.
The authors are grateful to Joseph J. Eron, Jr, Sonia Napravnik, and Alan Brookhart for their thoughtful comments and guidance and to Andrew Edmonds for inspiring the side-by-side box plot. The authors acknowledge the contributions from study staff and wish to thank study participants and their caregivers for their contribution to this study.
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HIV; tuberculosis; antiretroviral therapy; children; response to cART
Supplemental Digital Content
© 2014 by Lippincott Williams & Wilkins