Despite years of efforts to improve and simplify access to HIV diagnostics across a variety of key affected populations, late diagnosis remains a burning issue in the WHO European region. Depending on region, cohort and country, 30–60% of people living with HIV/AIDS (PLWH) in Europe enter care late, with hardly any significant improvement in these numbers over the last decade, except perhaps for men who have sex with men (MSM), where the introduction of pre-exposure prophylaxis has helped to increase rates of HIV testing overall, leading to earlier HIV diagnosis.[1,2] Populations who are particularly affected by late diagnosis across multiple studies include heterosexuals, women and migrants, especially of African descent, and people who use drugs.[3,4] Delay in HIV diagnosis and related late entry into medical care with clinical and immunological features of severe immunodeficiency are firmly associated with increased frequency of AIDS-defining opportunistic infections and malignancies, 10- to 13.6-fold higher mortality risk within 6 months from presentation and reduced life expectancy.[5,6] Late HIV diagnosis also notably reduces the benefit of reduced transmission risk related to early antiretroviral treatment initiation, while risk of comorbidities in PLWH associated with persistent inflammation remains higher and is often associated with a blunted immunological recovery. Within the current special issue themed 'Late diagnosis in HIV', a diverse range of topics around late diagnosis are covered, including updated epidemiology, risk factors for late diagnosis, revised definition of late diagnosis, impact of the COVID-19 pandemic, integration of phylogenetic models as well as novel testing approaches and a community perspective on late diagnosis.
The concept of late HIV diagnosis evolved from the original consensus definition on late presentation and advanced HIV disease published in 2010.[7] This definition had the aim to harmonizing data collection throughout Europe on late diagnosis and allowing cross-study or cross-country comparisons, improved surveillance and temporal trend analyses. The obtained consensus defined 'late presentation' as entering care with either a CD4 count < 350 cells/μL or an AIDS-defining event, regardless of the CD4 count, while 'advanced HIV disease' was defined as care entry with a CD4 count < 200 cells/μL or with an AIDS-defining event, regardless of the CD4 cell count.[7] This definition was widely adopted and, indeed, a plethora of clinical analyses on late presentation have been published subsequently. However, it became clear over time that certain aspects of the definition required further refinement. With the scale up of testing worldwide, identification of individuals with acute retroviral infection associated with a transient decrease in CD4 counts, and therefore possibly misclassified as late-diagnosed individuals, was becoming more common. Moreover, the new definition also uses new wording, as 'late presentation' has been associated with stigma within the community, whereas late diagnosis appears to be a more accurate technical term.
This special issue features the revised definition developed under the EuroTest initiative in collaboration with ECDC, the WHO Regional Office for Europe and the European AIDS Clinical Society (EACS).[8] The definition of late HIV diagnosis retained the CD4 count threshold of < 350 cells/μL and an AIDS-defining event, regardless of the CD4 cell count; however, reclassification into the 'not late' category is allowed based on the hierarchy of evidence of the recent infection (based on either laboratory markers, negative HIV test with the previous 12 months or symptoms of acute HIV illness).[8]
Exclusion of recent infections from population- level analyses allowed researchers to correct the total number of late-diagnosed cases to obtain more precise data. Such reclassification was successfully applied in the study by Kirwan et al., and allowed the calculated late diagnosis rate to be decreased by the overall factor of 14%.[9] The correction rates accounting for recent infection were highest among extensively tested populations (e.g. in MSM aged 15–24 years, the correction factor reached 46%), but were notably lower among populations known to be tested less frequently, such as heterosexually infected and/or older individuals.
Novel approaches for implementation of molecular data for validation of risk factors and timelines associated with late diagnosis and advanced HIV disease are also included in this issue. Determination of the number of late-diagnosed cases using the standard definition from 2010 supplemented with phylogenetically inferred time interval between HIV infection and diagnosis provides a valuable tool to infer the time between diagnosis and care entry.[10] Such an approach allows the importance of previously identified factors associated with late diagnosis of HIV to be reconfirmed, including older age and heterosexual transmissions, but it also allows the time between infection and diagnosis to be modelled across the transmission risk groups (0.63 years for people who inject drugs, 1.72 years for MSM and 2.43 years for heterosexually infected patients). It should be pointed out that the shorter time to diagnosis among people who inject drugs mostly reflects strategic intervention programmes in this particular group. Most interestingly, the risk of late diagnosis between migrants and native populations was similar.
Also presented within the framework of this special issue, general and COVID-19 pandemic specific data on epidemiological and mortality analyses add new insights to the topic of late diagnosis in the time of an ongoing pandemic with severe impact on HIV testing services.[11] Large-scale (1078 patients) epidemiological analysis from Belgium not only confirms the increased risk of late diagnosis among heterosexually infected groups, including patients of sub-Saharan origin, but also a higher frequency of renal impairment in newly diagnosed PLWH, which may be associated with persistent HIV-induced inflammation.[12] Notably, the association between late diagnosis and migration was also observed in a Spanish cohort of adolescents from the years 2004–2019, where adolescents born in Africa were associated with an increased odds ratio (OR) of late presentation [OR = 3.08, 95% confidence interval (CI): 1.38–6.79].[13] Late HIV diagnosis-associated mortality in the intensive care setting is presented in the study by Bakewell et al., with a mean 27% death rate in the late-diagnosed group, with adjusted relative risk of death of 1.75 (95% CI: 1.05–2.91) attributable to late diagnosis.[14]
It is widely known that the COVID-19 pandemic has negatively influenced timely HIV diagnosis, resulting in reduced access to ambulatory and specialist practices/checkpoint testing services and an increasing number of in-hospital diagnoses. In the study by van Bremen et al., not only was late HIV diagnosis notably more frequent in the pandemic period compared with the pre-pandemic year (83% vs. 59%, respectively; OR = 3.4, 95% CI: 1.18–9.83) but the rate of AIDS-defining conditions at diagnosis was also almost two-fold higher, whereas the median CD4 count dropped from 291 cells/μL (range 3–930) in the pre-pandemic period to 118 cells/μL (range 10–782) during the COVID-19 pandemic.[15] On the other hand, COVID-19 in-hospital diagnostics and treatment provided an unique opportunity for extended HIV testing in the general population. Within this issue, data from Polish hospitals' expanded HIV testing during the COVID-19 pandemic period are presented, with 5458 HIV tests conducted, yielding a positivity rate of 0.13%, 92% of delayed diagnoses, 76% with an AIDS-indicating condition and a median CD4 count of 72 cells/μL (range 3–382). HIV testing within the COVID-19 pandemic framework also allows refugee populations to be diagnosed; 44% of diagnosed patients were of Ukrainian origin.[16] Importantly, prolonged symptomatic time, not characteristic for COVID-19 infection [20.6 days (range 3–90 days)], was observed in a cohort, which may be indicative of the necessity for symptom-oriented HIV testing.
Finally, an important aspect in the fight against late diagnosis is related to the universal testing approaches, both within and outside the hospital settings. Valuable, large-scale (38 357 patients) Portuguese analysis presents data on the optimization of the universal HIV screening, implementing automated methodology within the emergency department (ED) setting. This screening strategy led to earlier diagnosis of patients, with the number of cases diagnosed late being significantly lower than historical controls, and diagnoses at higher CD4 counts (mean: 411 ± 253 cells/μL) compared with pre-programme controls (211 ± 150 cells/μL) and a clear reduction (20.5%) in the percentage of patients with missed opportunities for HIV diagnosis.[17] This approach is seconded by another large-scale UK-based study, which saw 78 333 HIV tests performed using an opt-out testing strategy, also within the ED setting and using a single patient serum sample, to decrease the analytical complexity and increase the testing uptake, reaching a testing coverage of up to 74.2% when all patients aged ≥ 16 years were included in this screening strategy. Not surprisingly, 60% of individuals were still diagnosed late but an added gain was the detection of acute HIV seroconversions in 16% of cases and 48% of new diagnoses in previously untested individuals.[18]
The late diagnosis supplement would not be complete without the perspective from the community delivered by Simon Collins' commentary. This short review includes community perspectives on why late diagnosis continues to occur and how it may be reduced. In addition, both structural barriers that prevent people from testing earlier and personal reasons as to why some people still refuse testing when it is offered are discussed critically.
In summary, late diagnosis still calls for unceasing actions, development and roll-out of novel simplified and stigma-free testing approaches, and innovative programmes. Expansion of testing, especially among migrant and heterosexual populations, is urgently warranted. We strongly hope that this special issue on late diagnosis, as well as the introduction of the new late diagnosis definition, will help to enhance further research in this area and to contribute to a much-needed decrease in the number of individuals in Europe who are diagnosed late.
HIV Medicine. 2022;23(11):1115-1117. © 2022 Blackwell Publishing
