Causes of Hospitalisation Over 2011-2018 Among a Cohort of People With HIV From a London Centre

Sophia M Rein (  sophia.rein.17@ucl.ac.uk ) Institute for Global Health, University College London (UCL) Royal Free Campus, Rowland Hill St London NW3 2PF https://orcid.org/00000002-5240-4838 Fiona C Lampe University College London Institute for Global Health Clinton Chaloner University College London Institute for Global Health Adam Stafford Royal Free London NHS Foundation Trust Alison J Rodger University College London Institute for Global Health Margaret A Johnson Royal Free London NHS Foundation Trust Jeffrey McDonnell University College London Institute for Global Health Fiona Burns Royal Free London NHS Foundation Trust; University College London Institute for Global Health Sara Madge Royal Free London NHS Foundation Trust Alec Miners London School of Hygiene & Tropical Medicine Lorraine Sherr University College London Institute for Global Health Simon Collins HIV i-Base Andrew Speakman University College London Institute for Global Health Andrew N Phillips University College London Institute for Global Health Colette Smith University College London Institute for Global Health


Background
Following the introduction of effective combination antiretroviral therapy (cART) in 1996, AIDS-related mortality and morbidity among people living with HIV (PLHIV) in high-income countries declined dramatically 1,2 . As life expectancy of PLHIV has continued to increase 3,4 , chronic conditions related to aging are increasingly prevalent 5,6 . This is re ected in the causes of hospitalisation among PLHIV, with non-AIDS conditions now accounting for an increasing proportion 7,8 .
Although there is previous work examining the trends over time and risk factors for hospitalisation, causes of clinical events have tended to be considered in broad categories. Monitoring the causes of hospitalisation among PLHIV in detail gives insight into changing patterns of morbidity, emerging new causes and current and future healthcare needs. However, few recent studies have comprehensively evaluated the detailed causes of hospitalisation in PLHIV in the contemporary treatment era, and, to our knowledge, none from the UK.
We describe the spectrum of ICD-10 classi ed causes of all hospitalisations occurring during a six-to-seven-year follow-up period, among 798 PLHIV recruited from a London centre in 2011-12.

Methods
The Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study recruited PLHIV from eight HIV outpatient clinics in England from February 2011 to December 2012 9 (North West London research ethics committee 10/H0720/70). The questionnaire was developed speci cally for the ASTRA study. Questionnaires for male and female participants can be found in the supplementary material.
A sub-study of hospitalisations was undertaken for participants from the Royal Free Hospital, London. Of 3,258 ASTRA participants, 899 (28%) were recruited at the Royal Free Hospital, of whom 809 (90%) consented to additional linkage of questionnaire data with routine clinical data 9 and 798 with follow-up data available were included. Data on hospitalisations occurring from the date of questionnaire completion (2011-2012; baseline) until 1 June 2018 was obtained using routine clinic data enhanced by a detailed review of electronic and paper Royal Free hospital medical records. Information was extracted on all admissions documented (including admissions at hospitals other than the Royal Free): dates of admission and discharge, the admitting hospital, whether the admission was classi ed as an emergency and the causes. Causes were classi ed into ICD-10 codes by an HIV clinician using discharge summaries and other relevant correspondence and information documented in the notes. Up to ve codes were assigned to every hospitalisation, therefore numbers can sum to more than 100%. Hospitalisations were de ned as overnight stays at the hospital. Repeated hospitalisations from individuals were included.
We previously reported on the association of baseline factors with subsequent hospitalisation 10 ; this report presents the causes of hospitalisation.

Causes of hospitalisation
Of the 274 hospitalisations, 174 had one cause assigned, 69 had two, 14 had three, 9 had four, 5 had ve causes and no information was available for 3 (415 causes in total). Figure 1 shows the distribution of causes.
The seven most common ICD-10 categories, which cover at least one cause for 196 (72%) of hospitalisations, are described below.
Digestive diseases were the second most documented cause, present in 13.1% (n = 36) of hospitalisations. Most common were diseases of: liver (n = 8 including: alcoholic hepatitis, hepatic failure, liver cirrhosis); gallbladder, biliary tract and pancreas (n = 6); intestines (n = 7 including: anal abscesses, stula of intestines, constipation, megacolon); oesophagus, stomach and duodenum (n = 4); other digestive diseases (n = 7). There were three admissions due to non-infective enteritis and colitis, three due to acute peritonitis, two due to appendicitis, and one due to hernia.
Of the hospitalisations for injury, poisoning and other consequences of external causes (n = 29, 10.6%), poisoning by drugs, medicines and biological substances was listed in 16 cases. Four were related to antiretrovirals; other substances included: non-steroidal anti-in ammatory drugs (NSAID), antiepileptic, sedative-hypnotic, antidepressants, psychostimulants, anticoagulants, calcium-channel blockers, antacids and anti-gastric secretion drugs, oxytocic drugs. Five of the hospitalisations due to poisoning were additionally recorded as intentional self-harm by self-poisoning with drugs/alcohol). Eight hospitalisations were related to complications of surgical and medical care including: infection or other procedure complications, and complications of internal orthopaedic prosthetic devices, implants and grafts. There were 19 injuryrelated causes (head, neck, thorax, abdomen, lower back, lumbar spine and pelvis, elbow and forearm, hip and thigh, knee and lower leg, ankle and foot and foreign body in the genitourinary tract).
For 27 (9.9%) admissions for genitourinary diseases, documented causes were: diseases of the urinary system (n = 7 including: urinary tract infections and urethral stulas), renal tubule-interstitial diseases (n = 5); diseases of male genital organs (n = 5). Other causes included renal failure, urolithiasis, non-in ammatory disorders of female genital tract and glomerular disease.
The remaining 12 ICD-10 categories were each mentioned in less than 9% of the total admissions (Fig. 1).
Of note, there were 11 hospitalisations related to mental health problems. Four were related to depressive episodes; three to use of alcohol, opioids or other stimulants; one to non-drug/alcohol induced delirium; four unspeci ed.
For injury/poisoning, more women (28%), particularly Black African women (21%), were hospitalised compared to the proportion overall (17% and 12% respectively). Infectious and genitourinary disease admissions had a higher proportion of heterosexual men (30% respectively), particularly of Black African ethnicity, compared to other causes. Median age at hospitalisation was somewhat lower for injury/poisoning than the other common causes.
Individuals hospitalised for digestive, infectious diseases or neoplasms had lower median CD4 counts compared to other causes. A prior AIDS diagnosis was much less prevalent in those hospitalised for injury/poisoning (28%) compared to other common causes and hospitalisations overall (51%); similarly CD4 nadir was higher for the injury/poising cause. Almost half of individuals admitted for infectious diseases had detectable viral load at hospitalisation compared to 21% of individuals admitted overall. Individuals admitted for circulatory, respiratory or infectious diseases were more likely to be current smokers compared to other causes.
The median duration of hospitalisation was 5 days, varying from 4 to 8 across the seven common causes.

Discussion
The causes of hospitalisation among a cohort of PLHIV followed up from 2011 to 2018 were wide-ranging with the most common being circulatory, digestive, respiratory, infectious diseases, injury/poisoning, genitourinary diseases and neoplasms in that order. AIDS-de ning conditions accounted for 10% of hospitalisations.
Two other European studies of PLHIV in the contemporary era found infections were the most common cause of hospitalisation, with non-AIDS infections at least as common as AIDS-related. A French study in PLHIV in 2011 found that non-AIDS infections were the most common cause of hospitalisation (16.4%), followed by HIV-related diseases (15.6%) 11 . A Spanish study also found that infectious diseases (35%, of which 36% were AIDS-related) were the most common causes of hospitalisation in 2003-13, followed by digestive and respiratory diseases, hepatic decompensations, non-AIDS malignancies, psychiatric illnesses and cardiovascular diseases (CVD) 12 . A global systematic review among PLHIV focusing primarily on the period 2007-2015 found that the most common admission causes for adults were ADIs (31% in Europe) and bacterial infections (27% in Europe) in all geographic regions. Other common causes in Europe were respiratory (14%), psychiatric (13%), cardiovascular (12%), renal (11%), and liver diseases (10%) 7 .
The spectrum of causes of hospitalisation in our study are similar to those found for mortality in PLHIV in recent studies in high income settings, [13][14][15] including a study of 206 deaths of PLHIV in London in 2016, suggesting a similar underlying pattern of morbidity not dominated by AIDS-de ning illnesses 13 .
In comparison to the 2018/19 National Health Service England data on hospitalisation in the general population, infections and circulatory disease admissions accounted for a larger proportion in our study of PLHIV, while pregnancy and childbirth were less common, which is expected given the lower proportion of women. Digestive diseases, neoplasms, respiratory diseases, injury/poisoning, circulatory, genitourinary and musculoskeletal diseases, and symptoms, signs and abnormal clinical ndings, were among the top ten causes both in our study and in the general population, with some difference in relative importance 16 . Although the comparison is complicated by demographic differences, this suggests the pattern of morbidity causing hospitalisation is broadly similar in PLHIV as in the general population, with persisting differences in admissions for infectious diseases.
Half of individuals in our study had previous AIDS at hospitalisation; this percentage was particularly high for admissions with infectious diseases as a cause, but was also over 50% for circulatory, digestive, respiratory, and neoplasm causes. Overall, 43% of those hospitalised had previous AIDS at baseline compared to 34% in the whole study population. Our previous ndings showed that baseline CD4 nadir predicted hospitalisation in this population 10 . The potential long-lasting effects of immunosuppression on a range of morbidities reinforces the importance of timely diagnosis and treatment for HIV.
The rate of hospitalisation of 5.8/100 person-years in our study population was lower than some other recent studies in other high income settings 11,17,18 . Our study population included a low proportion of individuals with recent diagnosis (3.6% diagnosed within one year) for whom hospitalisation rates are particularly high 19 .
Hospitalisations occurring at hospitals other than the Royal Free may have been missed if not reported to the HIV physician by the patient, general practitioner or hospital, or if this information was not documented. ASTRA participants may differ from non-participants with respect to levels and patterns of morbidity.
In summary, in the contemporary cART era, the spectrum of causes for hospitalisation in PLHIV in the UK highlights the importance of holistic care, including the prevention, early detection and treatment of common chronic conditions.

Declarations
Ethics approval and consent to participate Ethical approval for the ASTRA study was obtained from the North West London research ethics committee (10/H0720/70). Informed consent to participate in the ASTRA study was obtained from all participants. Basic consent to participate in the ASTRA study included permission to collect the latest CD4 count and HIV plasma viral load values (with dates) known to each participant and these details were recorded in the study log. Participants were also asked if they would consent to linkage of questionnaire data with their routine clinical data for this study over the next few years. They were told that this was an optional consent and that they could refuse and still participate in the questionnaire part of the study.

Availability of data and materials
Any personally identi able data cannot be made publicly available to protect participants' privacy. All other relevant data are available upon request to the senior author (contact: f.lampe@ucl.ac.uk).

Consent for publication
Not applicable.

Competing interests
No con icts of interest declared. CC, ASt were responsible for data collection. SMR drafted the rst draft of the manuscript, and all authors provided substantive input into this and subsequent drafts.