Abstract
Introduction
Timely diagnosis of HIV in children remains a challenge in all settings including low‐prevalence, high‐income countries (HIC). We aimed to characterize the prevalence of late diagnosis, and prior missed diagnostic opportunities among new presentations of paediatric HIV in HIC referred to an international Perinatal Virtual Clinic (PVC).
Methods
Retrospective analysis of new paediatric diagnoses in HIC, referred to the PVC between January 2018 and April 2025. Data on demographics, clinical features and HIV virology/immunology were extracted from standardized referral templates. Cases were categorized as late or non‐late diagnosis by age‐related CD4 thresholds, and the two groups compared.
Results
Among 45 new paediatric HIV diagnoses referred to the PVC from the European region (41), Australia (2) and Chile (2), the median age was 9 years (IQR 0.8–13); 66% (27/41) were migrants, predominantly from sub‐Saharan Africa; 39% (16/41) were born in HIC. Most (27/45;60%) were tested due to symptoms; 21/45 (47%) were diagnosed with AIDS. The median CD4 count was 230 cells/mm3 (IQR 24.5–531), viral load (VL) 316 000 copies/mL (IQR 65 150–1 315 000) with 31/45 (69%) meeting criteria for late diagnosis. Late‐diagnosed children had significantly higher VL (p = 0.02) and were more likely to have prior symptomatic healthcare encounters (p = 0.004).
Conclusions
Despite access to prevention and screening, late paediatric HIV diagnosis persists in HIC, with severe immunosuppression and missed opportunities for earlier recognition and treatment initiation. Improved implementation of family‐based screening, particularly following parental/sibling diagnosis or migration from endemic areas, and education of healthcare providers regarding HIV indicator diseases in children are essential.
Keywords: HIV screening, late diagnosis, missed opportunities, paediatric HIV, Perinatal Virtual Clinic
INTRODUCTION
By the end of 2023, an estimated 1.4 million children under 15 years were living with Human Immunodeficiency Virus (HIV) globally, with approximately 120 000 new paediatric infections in that year, more than 90% acquired perinatally (PaHIV) [1]. Early infant diagnosis and timely initiation of antiretroviral therapy (ART) remain extremely challenging in many settings and, without access to ART, approximately half the infants will die before their second birthday [2]. Conversely, 10%–15% will survive into adolescence with minimal symptoms [3]. This wide spectrum of disease presentation, results in children being particularly vulnerable to missed HIV diagnoses, especially in low‐prevalence settings. Within Europe, PaHIV is now a rare disease of childhood due to very high uptake of interventions to prevent vertical transmission, with most individuals with PaHIV having transitioned to adult care [4]. While 90% of children born with HIV live in Africa, global migration has led to over 50% of children living with HIV in Europe being migrants, the proportion rising over time [5].
Late diagnosis (LD) of HIV infection in adults is defined as a CD4 count ≤ 350 cells/mm3 or an AIDS‐defining condition at presentation, regardless of CD4 count; however a consensus definition for children is lacking [6]. LD in adults is associated with increased all‐cause mortality, both acquired immunodeficiency syndrome (AIDS) and non‐AIDS related, poorer immune recovery, increased risk of non‐infectious comorbidity, higher healthcare costs and risk of onward transmission [7, 8]. The impact of LD in children is less studied, but shows increased mortality and non‐infectious long‐term sequelae, including neurological, cardiorespiratory, growth and mental health issues [9, 10]. Within the United Kingdom (UK) perinatal cohort, having a childhood AIDS event was associated with an increased risk of mortality decades later, following transition to adult care [8]. Early initiation of ART in childhood has been associated with improved long‐term outcomes in adulthood despite an increased likelihood of being on second‐line therapy [11, 12]. Children who commenced ART at a younger age and higher CD4 count achieved better immune reconstitution compared to those initiating therapy after 10 years of age, who rarely achieve a normal CD4 count irrespective of CD4 count at treatment start [13].
A UK‐based multidisciplinary Perinatal Virtual Clinic (PVC), established in 2009, meets monthly to discuss complex case management related to HIV in pregnancy, childhood and adolescence [14]. While most cases discussed are from the UK (https://www.chiva.org.uk/professionals/clinic-networks/), international referrals are received through the PENTA network (https://penta-id.org/hiv/treatment-guidelines/).
This study describes the new paediatric HIV diagnoses referred to the PVC from HIC, aiming to identify the prevalence of LD and highlight missed opportunities for earlier diagnosis.
MATERIALS AND METHODS
Retrospective study of children and adolescents aged less than 18 years newly diagnosed with HIV and referred from low prevalence, HIC to the PVC, between January 2018 and April 2025. Information was collected from standardized anonymized forms completed by referring clinicians (https://www.chiva.org.uk/professionals/clinic-networks/).
Demographic variables included sex, age, country of birth and of residence. The reason for HIV testing was categorized as screening of asymptomatic children (usually following a parent/sibling diagnosis) or testing during the investigation of a symptomatic child. Perinatal transmission was assumed for diagnoses <18 years of age, with maternal HIV diagnosis or maternal death consistent with HIV, and no other risk factor for HIV acquisition. Clinical data included HIV viral load (VL), CD4 count, and HIV‐1 associated drug resistance mutations (DRMs) at diagnosis, AIDS‐defining conditions, WHO clinical staging and previous healthcare encounters. Children aged 5 years or older were classified as having LD or non‐late diagnosis (non‐LD) using the adult criteria. Children below 5 years were classified as having LD if they had an AIDS diagnosis and/or met age‐defined CD4 thresholds: ages 1 to 5 years, CD4 <500 or <20%; age <1 year, CD4 <750 or <25% [15, 16].
Data were summarized using medians and interquartile ranges (IQR) for non‐normally distributed continuous variables and frequencies and percentages for categorical variables. Mann–Whitney U test and Chi‐squared test (or Fisher's exact test) were used to assess differences in continuous and categorical variables, respectively. Statistical analysis was performed using Excel and SPSS Statistics 30.0. A p‐value of <0.05 was considered statistically significant.
Ethical approval was not required as per UK Health Research Authority guidance for routinely collected clinical data as part of an anonymized database for clinical decision‐making. All referrals submitted to the PVC are anonymized with individual data limited to age in years and country of birth/referral.
RESULTS
Of 530 cases presented at the PVC between January 2018 and April 2025, 45 (8.5%) were new diagnoses of HIV in a child/adolescent living in a HIC (Figure 1). The frequency of cases with a new HIV diagnosis referred per year was the highest in 2023 (13/45), followed by 2022 and 2024 (both with 8/45 cases) (Figure 1). Median age at diagnosis was 9 years (IQR 0.8–13), with 26.7% (12/45) being diagnosed below 1 year of age and 46.7% (21/45) above the age of 10 years (Table 1).
FIGURE 1.
Selection and distribution of PVC cases identifying new HIV diagnoses in high‐income settings. AIDS, Acquired Immunodeficiency Syndrome; HIC, High‐income Country; PVC, Perinatal Virtual Clinic.
TABLE 1.
Demographic, clinical and virological/immunological characteristics at HIV diagnosis.
| Characteristics | Population, N = 45 | Late diagnosis, N = 31 (68.9%) | Non‐late diagnosis, N = 14 (31.1%) | p‐value (LD vs. NLD) |
|---|---|---|---|---|
| Sex | 0.588 | |||
| Male | 22 (52.4%) | 16 (55.2%) | 6 (46.2%) | |
| Female | 20 (47.6%) | 13 (44.8%) | 7 (53.8%) | |
| Missing data | 3 | 2 | 1 | |
| Age | 0.432 | |||
| Median, years (IQR; range) | 9 (0.8–13; 0.1–16) | 11 (0.8–14; 0.3–16) | 7.5 (0.4–13; 0.1–16) | |
| Age group, years | ||||
| <1 | 12 (26.7%) | 8 (25.8%) | 4 (28.6%) | |
| 1–4 | 4 (8.9%) | 2 (6.5%) | 2 (14.3%) | |
| 5–10 | 8 (17.8%) | 5 (16.1%) | 3 (21.4%) | |
| 11–14 | 13 (28.9%) | 10 (32.3%) | 3 (21.4%) | |
| 15–17 | 8 (17.8%) | 6 (19.4%) | 2 (14.3%) | |
| Country of residence | 0.143 | |||
| United Kingdom | 29 (64.4%) | 17 (54.8%) | 12 (85.7%) | |
| Portugal | 4 (8.9%) | 4 (12.9%) | 0 | |
| Republic of Ireland | 3 (6.7%) | 3 (9.7%) | 0 | |
| Australia | 2 (4.4%) | 2 (6.5%) | 0 | |
| Chile | 2 (4.4%) | 2 (6.5%) | 0 | |
| Latvia | 2 (4.4%) | 2 (6.5%) | 0 | |
| Denmark | 1 (2.2%) | 0 | 1 (7.1%) | |
| Italy | 1 (2.2%) | 1 (3.2%) | 0 | |
| Netherlands | 1 (2.2%) | 0 | 1 (7.1%) | |
| Migrant status | 0.095 | |||
| Yes | 27 (65.9%) | 22 (73.3%) | 5 (45.5%) | |
| No | 14 (34.1%) | 8 (26.7%) | 6 (54.5%) | |
| Missing data | 4 | 1 | 3 | |
| Country of origin | 0.065 | |||
| Sub‐Saharan Africa | 21 (51.2%) | 16 (53.3%) | 5 (45.5%) | |
| Western Europe | 11 (26.8%) | 5 (16.7%) | 6 (54.5%) | |
| Eastern Europe | 5 (12.2%) | 5 (16.7%) | 0 | |
| Chile | 2 (4.9%) | 2 (6.7%) | 0 | |
| Australia | 1 (2.4%) | 1 (3.3%) | 0 | |
| Egypt | 1 (2.4%) | 1 (3.3%) | 0 | |
| Missing data | 4 | 1 | 3 | |
| Ethnicity | 0.098 | |||
| Black African | 23 (67.6%) | 16 (59.3%) | 7 (100.0%) | |
| White | 7 (20.6%) | 7 (25.9%) | 0 | |
| Black Caribbean | 2 (5.9%) | 2 (7.4%) | 0 | |
| Mixed | 2 (5.9%) | 2 (7.4%) | 0 | |
| Missing data | 11 | 4 | 7 | |
| Duration in the country of residence after migration before diagnosis | N = 27 | N = 22 | N = 5 | 0.027 |
| Median, years (IQR; range) | 1 (0.3–22; 0–11) | 1 (0.5–2; 0–11) | 0 (0–0; 0–0) | |
| <1 year | 10 (41.7%) | 8 (36.4%) | 2 (100.0%) | |
| 1–5 years | 10 (41.7%) | 10 (45.5%) | 0 | |
| >5 years | 4 (16.7%) | 4 (18.2%) | 0 | |
| Missing data | 4 | 0 | 3 | |
| Reason for HIV testing | <0.001 | |||
| Symptoms | 27 (60.0%) | 25 (80.6%) | 2 (14.3%) | |
| Screening | 16 (35.6%) | 6 (19.4%) | 10 (71.4%) | |
| Unclear | 2 (4.4%) | 0 | 2 (14.3%) | |
| Previous hospital admissions | 0.001 | |||
| Yes | 19 (51.4%) | 17 (70.8%) | 2 (15.4%) | |
| No | 18 (48.6%) | 7 (29.2%) | 11 (84.6%) | |
| Missing data | 8 | 7 | 1 | |
| Transmission route | 0.135 | |||
| Vertical | 40 (88.9%) | 26 (83.9%) | 14 (100%) | |
| Nosocomially acquired | 3 (6.7%) | 3 (9.7%) | 0 | |
| Unclear | 2 (4.4%) | 2 (6.5%) | 0 | |
| Viral load (copies/mL) | 0.020 | |||
| Median (IQR; range) | 316 000 (65150–125; 289–108) | 587 000 (192000–155; 7175–108) | 67 000 (22104‐297 751; 289–176) | |
| <100 000 | 14 (31.1%) | 6 (19.4%) | 8 (57.1%) | |
| ≥100 000 | 31 (68.9%) | 25 (80.6%) | 6 (42.9%) | |
| CD4 count (cells/mm3) | <0.001 | |||
| Median (IQR; range) | 230 (24,5–531; 2–2905) | 100 (14–287; 2–2136) | 661.5 (468–2266.5; 354–2905) | |
| <200 | 21 (48.8%) | 21 (67,7%) | 0 | |
| 200–350 | 7 (16.3%) | 7 (22,6%) | 0 | |
| 351–499 | 4 (9.3%) | 1 (3.2%) | 3 (25.0%) | |
| ≥500 | 11 (25.6%) | 2 (6.5%) | 9 (75.0%) | |
| Missing data | 2 | 0 | 2 | |
| WHO clinical staging | <0.001 | |||
| 1 | 15 (33.3%) | 4 (12.9%) | 11 (78.6%) | |
| 2 | 5 (11.1%) | 3 (9.7%) | 2 (14.3%) | |
| 3 | 6 (13.3%) | 6 (19.4%) | 0 | |
| 4 | 19 (42.2%) | 18 (58.1%) | 1 a (7.1%) | |
| AIDS‐defining conditions | <0.001 | |||
| Absent | 24 (53.3%) | 10 (32.3%) | 14 (100%) | |
| Present | 21 (46.7%) | 21 (67.7%) b | 0 | |
| HIV encephalopathy | 7 (33.3%) | |||
| PJ pneumonia | 6 (28.6%) | |||
| CMV disease | 4 (19.0%) | |||
| NTM infection | 4 (19.0%) | |||
| Candidiasis of LRT or oesophagus | 3 (14.3%) | |||
| Severe recurrent bacterial pneumonia | 3 (14.3%) | |||
| Tuberculosis | 2 (9.5%) | |||
| Kaposi sarcoma | 2 (9.5%) | |||
| HIV major DRMs | 0.586 | |||
| No | 29 (87.9%) | 20 (90.9%) | 9 (81.8%) | |
| Yes c | 4 (12.1%) | 2 (9.1%) | 2 (18.2%) | |
| Missing data | 12 | 9 | 3 | |
Abbreviations: CMV, cytomegalovirus; DRMs, drug resistance mutations; IQR, interquartile range; LD, late diagnosis; LRT, lower respiratory tract; NLD, non‐late diagnosis; NTM, non‐tuberculous mycobacterial; PJ, Pneumocystis jirovecii.
This patient did not fulfill the criteria for late HIV diagnosis, but at presentation had nephropathy, which resolved after initiating ART and was therefore classified as HIV‐associated nephropathy (WHO clinical stage 4).
Some patients had more than one AIDS‐defining condition; hence the total sum is larger than 21.
Three patients with a single non‐nucleoside reverse transcriptase inhibitors DRM (Y188L, G190A and V179E) and one with a nucleoside reverse transcriptase inhibitor DRM (M184MIV).
Country of Origin and Residence
Forty‐one out of forty‐five were diagnosed in the European region, mainly the UK (29/45; 64.4%), with additional cases from Australia (2/45) and Chile (2/45). Two thirds (27/41; 65.9%) were migrants, three quarters (21/27; 77.8%) from Africa, with 2 individuals born in a HIC subsequently migrating to another HIC prior to diagnosis. Among migrant children, the median duration of HIC residence prior to diagnosis was 1 year (IQR 0.3–2; range 0–11) (Table 1). Conversely, 16 children were born in HIC with access to vertical transmission‐prevention programs; in 6/16 (37.5%), parental seroconversion likely occurred in late pregnancy/breastfeeding post‐negative first‐trimester screening; one individual declined antenatal screening; one infant acquired HIV despite maternal viral suppression with extreme prematurity, prolonged rupture of membranes and chorioamnionitis; in 8/16 (50.0%), no information regarding parental HIV status during pregnancy was available.
Reason for Testing and Route of Transmission
Twenty‐seven out of forty‐five (60.0%) were tested due to symptoms, 16 (35.6%) diagnosed through family screening, with 2 undocumented (Table 1). For 40/45 (88.9%), the perinatal route of transmission was deemed likely. In three children with negative parental HIV screening, acquisition was likely nosocomially via blood transfusion in low‐income settings prior to migration; in two children, the route of transmission was unclear.
Immunology and Virology
Median VL at diagnosis was 316 000 copies/mL (IQR 65 150–1 315 000), with 31/45 (68.9%) having a VL ≥ 100 000 copies/mL. Baseline resistance testing was available for 33 (73.3%), four (12.1%) having single major DRMs as defined by the Stanford HIV database (https://hivdb.stanford.edu/); three to non‐nucleoside reverse transcriptase inhibitors (Y188L, G190A and V179E), and one to nucleoside reverse transcriptase inhibitors (M184MIV). Median CD4 count was 230 cells/mm3 (IQR 24.5–531), with 31/45 (68.9%) meeting immunological criteria for LD (Table 1).
Comparing Late and Non‐Late Diagnoses
Thirty‐one out of forty‐five (68.9%) had LD, with 21 (46.7%) presenting with an AIDS diagnosis (Figure 1). Between the LD and non‐LD groups, no statistical difference was found in age, sex, ethnicity, country of birth or migration status. Duration of residence in the HIC prior to diagnosis was significantly higher in the LD group (p = 0.027) (Table 1). A higher proportion of those with LD were symptomatic (25/31; 80.6%) compared to non‐LD (2/14; 14.3%) (p < 0.001). Individuals with late diagnoses were significantly more likely to have a VL ≥100 000 copies/mL (25/31; 80.6% vs. 6/14; 42.9%, p = 0.02).
Missed Opportunities for Earlier Diagnoses
Nineteen out of thirty‐seven individuals (51.4%) had one or more previous medical encounters with clinical features retrospectively attributable to HIV. Patients with LD were significantly more likely to have had previous healthcare admissions (HIC and/or birth country), compared to the non‐LD group (17/31; 70.8% vs. 2/14; 15.4%, p = 0.001).
Illustrative Case
A 15‐year‐old from Africa, resident in Europe for 1 year, not sexually active, second hospital admission within 6 months with pneumococcal pneumonia. Previously healthy, past shingles, with body mass index of 22.9 kg/m2. Baseline VL 587 000 copies/mL and CD4 count 29 cells/mm3. Further investigation confirmed Pneumocystis jirovecii pneumonia, cytomegalovirus viraemia, cryptosporidiosis, oral herpes simplex and candida infections. Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) commenced and, at 3 weeks immune reconstitution inflammatory syndrome developed, with atypical mycobacteria identified in a superficial abscess, and ethambutol and azithromycin added. At 1 year, VL < 50 copies/mL and CD4 count 457 cells/mm3. After presentation, mother was also diagnosed with HIV, reporting negative antenatal screening, but had breast fed for 2 years.
DISCUSSION
Approximately two‐thirds (69%) of children and adolescents newly diagnosed with HIV referred to the PVC from low‐prevalence, HIC were diagnosed late, presenting with advanced disease, severe immunosuppression, and AIDS‐defining conditions. This number contrasts with the proportion of LD in the adult population in Europe, around 52% in 2023, and emphasizes the need for a low index of clinical suspicion, and better screening programmes in the paediatric population [17]. Half the children had prior medical encounters with HIV‐related symptoms or a known family history of HIV, highlighting significant missed opportunities for earlier diagnoses [18]. The largest number of cases per year was presented in 2023 (13/45), which is in line with WHO data showing an increase in new diagnoses in 2023, probably due to improved testing efforts and a rebound in HIV testing after the COVID‐19 pandemic [17].
Two‐thirds (66%) were migrants, mostly from Africa, and half had resided in the HIC for over a year prior to diagnosis, suggesting post‐migration gaps in screening and/or integration into healthcare services. In a large European cohort (n = 2620), comparing migrant and non‐migrant children living with HIV, the former were older and more severely immunocompromised at diagnosis, but virological and immunological outcomes at one year of ART were comparable [5]. These results are reassuring but do not consider longer‐term outcomes, differences in non‐HIV‐related morbidity and economic burden. Findings from paediatric trials support that early‐life immunological compromise and delayed initiation of ART are linked to poorer immune reconstitution, persistent immune dysregulation, and increased long‐term non‐AIDS comorbidities and mortality [5, 12, 13].
Almost 40% were born in HIC with access to antenatal vertical‐transmission prevention. Parental seroconversion during late pregnancy or breast feeding was identified as a potential contributing factor, reinforcing the importance of testing children following parental diagnosis, even if antenatal screening was negative. While not preventive, this strategy facilitates earlier diagnosis and timely initiation of ART. Sociocultural barriers, including HIV‐related stigma, may lead to refusal of testing, particularly among individuals from high‐prevalence settings [2]. It is essential that healthcare professionals offer prenatal testing to all pregnant individuals and subsequently consider WHO recommendations for pre‐exposure prophylaxis in pregnant and breastfeeding people at substantial risk for HIV acquisition, to prevent parental seroconversion and subsequent vertical transmission [19].
Baseline DRMs were documented in four individuals, suggesting either transmitted DRMs or unreported prior ART exposure. This finding supports the importance of routine baseline resistance testing in all newly diagnosed children, especially when parental ART history is unknown [11, 12]. While first‐line therapy based around a second‐generation integrase inhibitor remained effective in all cases, ongoing surveillance is required with the emergence of integrase resistance. DRMs in children with no known ART history potentially suggest that caregiver reports may not always be reliable, due to stigma or limited awareness, and it is common for paediatric medical histories to be incomplete in cases of migration or adoption [2].
This study is limited by retrospective design and small patient sample, with some data missing from referral forms, although standardized templates helped minimize this. Most diagnoses occurred in the UK, potentially skewing geographic representation. The PVC was initially established in 2009 as a clinical network to improve paediatric HIV care and for the approval of high‐cost paediatric ART in the UK [14]. Over the last decade international referrals have increased through the PENTA Network, typically in regions where PENTA training courses have occurred (https://training.penta-id.org/) and may introduce further geographical bias. Cases presented at the PVC likely reflect more severe or complex scenarios, potentially over representing the burden of LD. Nonetheless, our findings highlight critical points for reflection, particularly the need to further improve prevention of PaHIV worldwide, with timely HIV screening and diagnosis at first clinical presentation in HIC, both in migrant and non‐migrant populations [19, 20]. Many European paediatricians with experience in HIV care are now reaching the age of retirement, highlighting the ongoing need for paediatric healthcare professional education, including recognizing indicator diseases for HIV, and the importance of blood‐borne virus screening for children. Multidisciplinary forums, such as the PVC, facilitate collaboration across institutional and geographical boundaries with the aim of optimizing healthcare for individuals, and providing opportunities for healthcare professionals to build skills in managing HIV. This remains one of the few studies addressing LD of paediatric HIV specifically in HIC. Future research should focus on prospective, multicentre studies to better characterize the epidemiology of LD and prompt the implementation of targeted screening, timely diagnosis and initiation of treatment.
AUTHOR CONTRIBUTIONS
Carolina Curto collected the data and wrote the draft. M. Tritzali assisted with data collection and writing the draft. A. Bamford, A. C. Bailey, E. G. H. Lyall, N. E. Mackie, N. Tickner are on the PVC committee and reviewed the draft. C. Foster devised the article, chairs the PVC and reviewed the drafts.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ACKNOWLEDGEMENT
Open access publication funding provided by FCT (b‐on).
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.