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. Author manuscript; available in PMC: 2025 Feb 24.
Published in final edited form as: Curr Opin HIV AIDS. 2018 Nov;13(6):501–506. doi: 10.1097/COH.0000000000000500

HIV-associated pediatric tuberculosis: prevention, diagnosis and treatment

Alexander Kay a,b, Anthony J Garcia-Prats c, Anna Maria Mandalakas a
PMCID: PMC11849721  NIHMSID: NIHMS2040461  PMID: 30286040

Abstract

Purpose of review

The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH) who shoulder a disproportionate burden of all child TB mortality.

Recent findings

CALWH benefit less from Bacille– Calmette Guerin vaccination than HIV-uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH. Finally, antiretroviral and anti-TB drug interactions continue to complicate cotreatment for children. Despite these challenges, recent data fuel a new awareness of TB as a hidden cause of child mortality and a renewed commitment to TB prevention. New diagnostic approaches using existing tools with novel specimens, such as stool, may improve the diagnosis of TB in CALWH. Further, pharmacokinetic studies and the development of new drug formulations promise better treatment options for CALWH in the near future.

Keywords: diagnosis, HIV, pediatric, treatment, tuberculosis

Summary

With the awareness that TB is the leading cause of mortality among CALWH, comes a responsibility to accelerate research to prevent, diagnose and treat TB in this vulnerable population. In the present, we must adopt evidence-based preventive and treatment strategies to enhance outcomes of CALWH and combating TB.

INTRODUCTION

The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH). Recent modeling advances estimate that 17% of all child TB mortality occurs in CALWH [1]. CALWH benefit less from Bacille–Calmette–Guerin (BCG) vaccination than HIV uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH. Finally, antiretroviral and anti-TB drug interactions continue to complicate cotreatment for children. Despite these challenges, recent data fuel a new awareness of TB as a hidden cause of child mortality and a renewed commitment to TB prevention. New diagnostic approaches using existing tools with novel specimens, such as stool, may improve the diagnosis of TB in CALWH. Further, pharmacokinetic studies and the development of new drug formulations promise better treatment options for children with TB and HIV in the near future. Here, we outline new developments in the prevention, diagnosis and treatment of TB/HIV coinfected children.

PREVENTION

The prevention of TB among CALWH can be informed by the epidemiology of the dual epidemics. Recent evidence confirms increased TB risk among people living with HIV (PLWH) who comprise 22% of TB deaths and 10% of TB disease [2,3]; global estimates are not available in CALWH. Recent notified data from 1800 Ghanaian TB patients demonstrated an 18% overall prevalence of HIV/TB coinfections which increased to 27% in children below 15 years of age [4]. Similarly, among 12 000 eSwati household TB contacts, TB was more common in contacts less than 5 years [odds ratio (OR) = 2.0], or HIV-infected contacts (OR = 4.9) [5].

BCG vaccination remains the oldest and most widely used child TB preventive intervention. Although robust cohort evidence from South Asia, Africa and South America demonstrated BCG vaccination rates ranging between 87 and 100% in resource-poor settings [6], guidelines recommend against BCG vaccination in newborns with known HIV infection because of concerns regarding disseminated BCG disease and adverse effects [3]. In addition to potentially increased effectiveness, recombinant BCG vaccines may also be safer, which is particularly important for HIV-infected children. Among HIV-unexposed South African newborns, the recombinant Mycobacterium bovis BGC vaccine VPM1002 (n = 36) was shown to have immunogenicity and safety parameters comparable to BCG Danish strain (n = 12) [7]. In addition to validation of these findings in a larger study, replication of this study in HIV-exposed and HIV-infected infants may improve the safety and effectiveness of TB vaccination in CALWH.

Although antiretroviral therapy (ART) is well recognized to prevent TB among PLWH, prior data on CALWH have been conflicting. A recent systematic review and meta-analysis of 22 cohorts of CALWH demonstrated a 5.0-fold increased TB incidence [95% confidence interval (CI) 4.0–6.0] in children with severe compared to nonsignificant immunosuppression, and lower TB risk in children on ART vs. not on ART (hazard ratio: 0.30, 95% CI 0.21–0.39) [1] indicating a clear risk reduction from ART. Further, following ART initiation, TB incidence declined over 12 months toward a hazard ratio of 0.1 (95% CI 0.04–0.25) [1]. Recent evidence also illustrates that adolescents attending an adolescent-friendly clinic had higher retention in care and viral suppression compared to adolescents attending the standard pediatric clinic [8].

The WHO End TB strategy prioritizes tuberculosis preventive therapy (TPT) as a critical tool to achieve elimination [2]. Nevertheless, in 2016, only 12 of the 30 TB/HIV high burden countries provided data on TPT, with reported TPT coverage among people newly enrolled in HIV care ranging from 2.4% in Indonesia to 73% in Zimbabwe [3]; rates specific to CALWH were not reported. Despite the slow rollout of TPT globally, accumulating evidence confirms the protective effect of old and new regimens. A meta-analysis of 61 studies including adults and children receiving TB preventive therapy found a reduced odds of incident TB for all regimens evaluated vs. placebo, including isoniazid for 6 months (OR, 0.65) or 12– 72 months (OR, 0.50), rifampicin-only (OR, 0.41), rifampicin-isoniazid for 3–4 months (OR, 0.53), rifampicin-isoniazid-pyrazinamide (OR, 0.35) and rifampicin-pyrazinamide (OR, 0.53). Weekly rifapentine-isoniazid compared with no treatment was also associated with reduced odds of TB (OR, 0.36). HIV status did not alter treatment efficacy of any regimen [9▀].

The REALITY factorial open-label trial conducted in Uganda, Zimbabwe, Malawi and Kenya provides critical evidence to guide TB prevention among CALWH [10]. Among ART-naive adults and children above 5 years of age with CD4+ counts less than 100, the study compared the effects of standard prophylaxis (trimethoprim-sulfamethoxazole alone) and enhanced antimicrobial prophylaxis (trimethoprim-sulfamethoxazole and 12 weeks isoniazid-pyridoxine, 12 weeks fluconazole, 5 days azithromycin and single-dose albendazole). Kaplan–Meier analysis at 24 weeks demonstrated a lower rate of death with enhanced prophylaxis than standard prophylaxis (8.9 vs. 12.2%; hazard ratio 0.73); at 48 weeks, death rates remained lower with enhanced compared to standard prophylaxis (11.0 vs. 14.4%; hazard ratio 0.76). The enhanced-prophylaxis group had significantly lower rates of TB (P = 0.02), death of unknown cause (P = 0.03) and new hospitalization (P = 0.03). Although children represented only 4% (72/1805) of the study population precluding subgroup analysis, evidence should be generalizable to children older than 5 years of age.

HIV-infection is a powerful risk factor for child TB and child TB mortality [11▀]. Although new evidence is not available, it is well recognized that this risk can be mitigated through early diagnosis of HIV and initiation of ART. As countries adopt test and treat strategies for ART, differentiated models of HIV care should be implemented that incorporate TB screening, diagnostics and preventive therapy tailored to meet the unique needs of CALWH.

DIAGNOSIS

TB is challenging to accurately diagnose in CALWH and difficult to confirm in children with and without HIV. GeneXpert Ultra (Ultra) is a new diagnostic tool recently introduced. A retrospective analysis of children evaluated for TB found that in children with a positive GeneXpert MTB/RIF (Xpert), Ultra or TB culture, Xpert detected 48/76 (63.2%; 95% CI 51.3–73.9), Ultra 56/76, (73.7%; 95% CI 62.3–83.1) and culture 63/76 (82.9%; 95% CI 72.5–90.6) [12]. The sensitivity of Ultra was similar in CALWH and HIV-uninfected children (66.7 and 67.7%; P = 0.935). Although there was no statistical difference between Xpert and Ultra, larger cohorts are needed. Recently, the WHO recommended Ultra in children based on possible increased sensitivity, and perceptions that reduced specificity are less of a limitation in this population [13,14].

The lipoarabinomannan (LAM) assay is recommended in CALWH who have severe HIV-related immunosuppression or severe TB disease symptoms [15]. However, this recommendation is based on adult data despite prior studies indicating poor sensitivity and specificity of LAM among CALWH [16]. Of note, recent prospective studies in an acutely ill cohort of hospitalized children (N = 137) living with HIV (CLWH) argue that LAM may have utility in this population [17▀,18]. A positive LAM was associated with death [adjusted hazard ratio (aHR), 4.92; 95% CI 1.79– 13.49]. The risk of death was greatest among children with unconfirmed TB (hazard ratio, 10.4; 95% CI, 0.94–115.18; P = 0.06), who may have experienced diagnostic delays associated with negative results of respiratory specimen testing. In the same cohort, the sensitivity of LAM was 45% (95% CI 10–82%) overall and highest in children less than 24 months of age (67%; 95% CI 9–95%) or with severe immunosuppression (71%; 95% CI 29–96%) [18]. The specificity of LAM was 91% for the entire cohort. These data suggest that LAM has utility as an adjunctive test among seriously ill CLWH. The ease of LAM implementation further increases the potential impact of this diagnostic test, particularly in settings where sputum specimen collection is underutilized.

Emerging evidence also points to the diagnostic value of Xpert testing employing stool specimens. Among the same cohort of hospitalized CLWH, stool Xpert diagnosed 5/8 (63%; 95% CI 25–92%) of children with confirmed TB, which was similar to the sensitivity of Xpert on traditional specimens [18]. In children with severe immunosuppression, the sensitivity of stool Xpert increased to 80%. In contrast, another prospective hospital-based diagnostic study found stool Xpert positive in 23/72 (32%) of children with confirmed disease, and in 23/51 (45%), with confirmed disease that was defined as severe [19]. The lower estimate of stool Xpert sensitivity in this study may be attributed to differential bias introduced by repeated testing of multiple respiratory specimens; the sensitivity improved to 45–50% when compared to a single respiratory culture with a remarkable additional yield from stool Xpert of 18–33%. HIV infection was not associated with stool Xpert performance in this study. Notably, stool Xpert only detected rifampin resistance in 3 of 12 (25%) cases with confirmed resistance, and culture of stool for TB performed poorly [19,20]. These data emphasize the need for new techniques to assess molecular drug resistance of Mycobacterium tuberculosis detected in stool. Finally, a recent study of children 5–16 years demonstrated the utility of stool Xpert in an ambulatory population [21]. In this cohort, stool Xpert was positive in 68% (13/19) of all confirmed cases and 77% (10/13) of confirmed cases in CALWH. Overall, these data suggest that stool testing via Xpert affords a promising diagnostic approach among CALWH, particularly among acutely ill children and in settings where the capacity to obtain traditional specimens is limited.

New evidence also suggests a potential role of ultrasonography as a diagnostic adjunct in CALWH [22]. Among 102 hospitalized children with confirmed or clinically diagnosed TB, ultrasonography detected splenic microabscesses in 38% (12/34) of CALWH vs. 19% of HIV uninfected children (P = 0.04). Among children with TB diagnosed clinically in the absence of radiographic features of TB, 40% of children had either lymphadenopathy or splenic microabscesses detected by ultrasound. Although the study design precluded estimation of the prevalence of sonographic abnormalities in children evaluated for TB, the results suggest that ultrasound may be a useful imaging adjunct to chest radiograph (CXR), or in the absence of CXR, for the diagnosis of TB in CALWH.

OUTCOMES AND TREATMENT

Outcomes among TB/HIV coinfected children remain suboptimal. A retrospective cohort study of 386 TB/HIV coinfected children (median age 5.7 years; IQR 2.0– 9.7) from 14 sites in Africa and Asia demonstrated that 308 (80%) had favorable outcomes and 30 (8%) died; higher weight-for-age Z-score was associated with reduced odds of unfavorable outcome (OR 0.35; 95% CI 0.67– 0.94) [23]. Notably, 22% of cases were treated with a three-drug regimen, omitting ethambutol, despite WHO recommendations to use an ethambutol-containing four-drug regimen in HIV-infected children. Of 286 ART-naive children at TB diagnosis, only 46% started ART within 8 weeks, and 13% did not start ART during the entire study period. Among ART naive children alive at 8 weeks post-TB diagnosis, 64% of those with favorable outcomes initiated ART in the first 8 weeks compared to 40% those with unfavorable outcomes (P = 0.04). Despite limitations of these observational data, this evidence provides support for early ART initiation and highlights the need for improving uptake of this important treatment recommendation.

In a systematic review and meta-analysis, child TB case fatality ratios (CFRs) were calculated in different eras (prior to 1946, 1946–1980, after 1980) and stratified by receipt of treatment (yes or no), age (0–4 years, 5–14 years) and HIV status [24]. Among children with TB in the pretreatment era, the pooled CFR was 21.9% (95% CI 18.1–26.4), with children 0–4 years of age having a higher CFR (43.6%; 95% CI 36.8–50.6) than children 5–14 years (14.9%; 95% CI 11.5–19.1). In the recent era when most children received treatment, the CFR was very low (0.9%; 95% CI 0.5–1.6). Although data were insufficient to calculate pooled CFRs for HIV-infected children, data suggested CFRs were higher in HIV-infected children receiving TB treatment both without ART (14.3%) and with ART (3.4%). This evidence clearly demonstrates the increased risk of TB mortality among younger, untreated and HIV-infected children.

There remain important questions about the optimal treatment of both TB and HIV in coinfected children. In 2010, revised guidelines recommended the use of higher doses of isoniazid and rifampicin in children [25]. An observational pharmacokinetic study in Ghana evaluated exposures of the first-line TB drugs in children receiving these revised WHO-recommended doses [26]. Among child participants (N = 100; 49% <5 years of age; 50% HIV-infected), HIV-infection was associated with low rifampicin maximum concentrations (Cmax) (aOR 2.45; 95% CI 1.01–5.95) and low ethambutol Cmax (aOR 5.37; 95% CI, 1.87– 15.37). The association of HIV-infection with low TB drug concentrations has been previously reported, but is not a consistent finding [27,28]; potential causes include reduced absorption or more rapid clearance due to HIV-infection and drug–drug interactions. A separate analysis of this same cohort with an additional 13 children treated for TB but not with revised WHO doses reported similar findings [29]. HIV-infection was associated with increased clearance and reduced exposures for rifampicin, pyrazinamide and ethambutol. This report again raises the possibility that TB drug concentrations may be adversely affected by HIV-infection and future studies may be warranted.

Optimal ART treatment in TB cotreated children remains problematic, largely because of drug–drug interactions with rifampicin. There have been little new data in this area in the last few years, despite an urgent need. A recent review highlighted limitations of existing evidence and priority research questions to optimize ART strategies for TB cotreated children [30].

Drug-resistant TB threatens global TB control, and there is a growing awareness of the burden in children. HIV-infected children with drug-resistant (DR)-TB have a high risk of poor outcomes. A retrospective cohort study of children treated for DR-TB from 2005 to 2008 at five South African hospitals (N = 423 children; median age 10.7 years, IQR 5.5–15.3; 56% HIV-infected of whom 68% received ART; 98% culture-confirmed, indicating relatively severe disease) reported a CFR of 16% [31]. Mortality was associated with HIV-infection (aHR 2.28; 95% CI 1.11–4.68). Although this association of HIV-infection with mortality is consistent with previous reports [32], the risk may be lower than reported here among children with less severe disease and better access to ART.

Efforts continue to develop shorter, safer, bettertolerated regimens for DR-TB treatment that are largely dependent on repurposed (linezolid and clofazimine) and novel TB drugs. Pediatric delamanid and bedaquiline trials are ongoing; preliminary trial results informed WHO recommendation for delamanid use in children 6–17 years of age [33]. There are clinically relevant drug–drug interactions between bedaquiline and efavirenz and ritonavir-boosted protease inhibitors, and potential interactions between clofazimine and a number of antiretrovirals. There are limited data currently to inform evidence-based pediatric recommendations; however, practical guidance based on expert opinion has been disseminated until more evidence is available [34].

RESEARCH PRIORITIES IN CHILDREN AND ADOLESCENTS LIVING WITH HIV

There are significant gaps in the evidence informing the care and treatment of CALWH and TB. Despite important new evidence, urgent priorities exist in every research domain as outlined in Table 1.

Table 1.

Summary of recent key evidence and research priorities for the diagnosis, prevention and treatment of HIV-associated tuberculosis in children

Recent key evidence Research priorities
Epidemiology CALWH continue to have increased risk of TB morbidity and mortality and account for 17% of all child TB deaths Describe and monitor the burden of TB infection and disease, socio-economic impact and treatment issues for CALWH
Prevention Among HIV-unexposed newborns, the recombinant Mycobacterium bovis BCG vaccine VPM1002 has immunogenicity and safety parameters comparable to BCG Danish strain and lower incidence of abscess formation
TB incidence is five times higher in CALWH with severe compared to nonsignificant immunosuppression
HIV-infection does not diminish the protective effect of TPT which decreases the odds of TB by 35–75%		 Develop a vaccine to be given to HIV-infected and exposed neonates, children or adolescents that improves on the safety and efficacy of BCG
Conduct pharmacokinetic and safety studies of new preventive drug regimens in CALWH to inform optimal dosing
Evaluate shorter and simplified preventive drug treatment regimens for DR and MDR TB infection in CALWH
Diagnosis Urine LAM predicts mortality in acutely ill hospitalized CALWH
Stool GeneXpert performs well in CALWH who are acutely ill, as well as in the outpatient setting
Abdominal ultrasound findings may provide incremental yield to CXR to assist in the clinical diagnosis of CALWH		 Establishing additional evidence for the use of urine LAM in children
Establishing protocols for introducing stool as an adjunct diagnostic specimen for TB, including stool processing protocols and drug resistance testing
Prospectively investigate the performance of ultrasonography as a diagnostic adjunct in CALWH
Treatment and outcomes Implementation of recommended care of TB-HIV-infected children, especially early initiation of ART, remains suboptimal
Improved ART strategies for TB-HIV coinfected children treated with rifampicin are still urgently needed		 Evaluate the PK, safety and optimal dosing of new ARVs such as raltegravir and dolutegravir in rifampicin treated children
Evaluate the PK, safety of new TB drugs such as bedaquiline, delamanid, clofazimine and linezolid with optimal ART in HIV-infected children with MDR-TB
Health systems Adolescents attending adolescent-friendly clinics have higher retention in care and viral suppression compared to adolescents attending standard pediatric clinics Determine the most appropriate and cost-effective TB/HIV integrated service delivery models for CALWH
Identify pragmatic, scalable and differentiated community-based strategies for TB screening, preventive therapy and treatment to enhance early entry and retention in the cascade of care
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ART, antiretroviral therapy; ARVs, antiretrovirals; CALWH, children and adolescents living with HIV; CXR, chest radiograph; DR, drug-resistant; MDR, multidrug-resistant; PKs, pharmacokinetics; TB, tuberculosis; TPT, TB preventive therapy.

CONCLUSION

Recent evidence reveals child TB as a hidden epidemic disproportionately affecting CALWH. With this awareness comes a responsibility to accelerate research aimed at the prevention, diagnosis and treatment of TB in this highly vulnerable population. Drawing upon recent evidence informing TB care and treatment of CALWH, we have outlined research priorities promising breakthroughs in the next decade. In the present, we must adopt evidence-based strategies for the prevention and treatment of TB and HIV in coinfected children.

KEY POINTS.

  • The detrimental synergy of colliding HIV and TB epidemics is most devastating among CALWH who contribute to 17% of all child TB mortality.

  • CALWH benefit less from BCG vaccination than HIV uninfected children and are not receiving TB preventive therapy despite global recommendations.

  • Urine lipoarabinomannan assays and stool GeneXpert are valuable diagnostic adjuncts to traditional TB specimens particularly in CALWH.

  • CALWH may be at higher risk of subtherapeutic rifampicin and ethambutol levels using WHO recommended doses.

  • Initiation of ART within 2 months of TB treatment initiation is associated with successful TB treatment outcomes for CALWH.

  • With the awareness that TB is a leading cause of mortality among CALWH, comes a responsibility to accelerate research aimed at the prevention, diagnosis and treatment of TB in this highly vulnerable population.

Acknowledgements

We would like to thank Mrs. Patricia Dorman for her assistance with the preparation of this review.

Footnotes

Financial support and sponsorship

This work was supported by Texas Children’s Hospital and the Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. A.K. is supported by the Thrasher Research Fund.

Conflicts of interest

The authors have no conflicts of interest to report.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▀of special interest

▀▀ of outstanding interest

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