Introduction

In the era of effective combination antiretroviral treatment (cART) more than half the causes of death in HIV positive patients are non-AIDS related [1]–[5], the most common being non-AIDS defining cancers, cardiovascular disease and liver disease.

High rates of suicide and accidental or violent death have also been described in HIV infected populations including in those receiving effective cART [6]–[8]. The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort reported suicide as the cause of death in 4% of deaths, with a further 2.5% attributed to drug overdose and 1.5% as accident [9]. In CASCADE, suicide was reported in 6.4% of deaths, violence in 3.3%, and 5.7% of deaths were attributed to substance abuse [10].

In the early years of the HIV epidemic, poor prognosis was a key contributing factor to high rates of suicide. Common experiences of HIV positive people such as stigmatisation, discrimination, social isolation, anxiety and depression, as well as frequent substance abuse, were also identified as contributory factors to suicide risk. Yet, despite the significant improvement in prognosis since the introduction of cART the rates of suicide remain high. This was demonstrated in the Swiss HIV Cohort Study where rates of suicide decreased substantially in the cART era compared to the pre cART era but still remained well above that observed in the general population [6].

In the Swiss HIV Cohort Study, the majority (>75%) of patients who committed suicide in the cART era had a diagnosis of mental illness with depression being the most common (>80%). A significant proportion (23%) of patients who died by suicide in the cART era had untreated mental illness. In this cohort, suicide rates were shown to decline with increasing CD4 cell counts. Advanced clinical stage (using the US Centres for Disease Control and Prevention classification system [11]) was significantly associated with suicide risk in both pre- and post-cART eras, after adjustment for other socio-demographic factors and history of psychiatric treatment. However, CD4 cell count and other HIV related factors were not included in this risk factor analysis. In the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) study, latest CD4 cell count was not significantly associated with violent causes of death. As with the Swiss HIV Cohort Study, the CASCADE study did not assess risk factors for suicide which take into account both HIV related factors and general risk factors for suicide in one model.

The extent to which HIV infection is also associated with increased risk of suicide or violent death is not well documented. Specifically the relative contribution of HIV related factors such as immune deficiency, as well as aspects of treatment neuroprotection/ neurotoxicity (e.g. cerebro-spinal fluid (CSF) penetrating/non penetrating ART) compared to accepted psychosocial risk factors has not been described in detail. Recent qualitative models of suicidality in HIV populations in the post cART era also incorporate synergistic effects of HIV related factors and ageing [12].

Most HIV-related studies of suicide focus on suicidality as an endpoint [13]. This obviates difficulties associated with low prevalence of suicide cases, case finding and retrospective data collection. However, there are important differences between determinants of suicidal ideation and suicide. For example, in a study of British private households, Gunnell et al found differences in the risk pattern of suicidal thoughts compared to completed suicide according to gender and age [14]. In that study the incidence of suicidal thoughts was seen to be over 200 times greater than the incidence of suicide. In this study we analysed determinants of confirmed cases of suicide as well as of accidental or violent death to develop adjusted models of risk associated with both psychosocial and HIV-related factors.

Methods

Results

Patient characteristics

A total of 81 patients were included in this analysis – 27 cases and 54 controls. Of cases, 17 (63%) were classified as death by suicide with mode of suicide by hanging (5 deaths) and drug overdose (5 deaths) being the most common (Table 1). A further 10 cases (37%) were classified as violent or accidental death, with death with associated drug overdose (8 deaths) being the most common. All cases were male, with a mean age of 41.6 years compared with 41.1 years for controls. Most deaths occurred prior to 2006 (61.6%) and mode of HIV exposure was either MSM (92.6%) or MSM/IDU (7.4%) (Table 1).

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Table 1. Characteristics used for case control selection¹.

https://doi.org/10.1371/journal.pone.0089089.t001

Patient characteristics prior to case death are shown in Table 2. Cases generally recorded higher levels of risk factors for suicide or violent death. Of social and demographic risk factors, cases were less likely to be in full time employment (59.3% vs. 35.3%), and more likely to live alone or in an institutional environment (55.6% vs. 25.9%). Of mental health, neurocognitive and other medical risk factors, cases were more likely to have a record of suicidal ideation (55.6% vs. 20.4%) and to have an increased number of recorded mental and cognitive and other clinical risk factors (>2 conditions ever recorded (29.6% vs. 11.1%)). Of HIV specific factors, cases were less likely to have recent CD4 count ≥500 cells/µL (18.5% vs. 46.3%). Cases were more likely to have been HIV-positive prior to 1990 (44.4% vs. 22.2%).

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Table 2. Patient characteristics prior to case death and risk of suicide and accidental/violent death¹.

https://doi.org/10.1371/journal.pone.0089089.t002

Multivariate analysis

To facilitate fitting of the multivariate model given low numbers of observations, certain inclusion variables were dichotomised. A multivariate model was initially fit with recorded recent full time employment (FTE) (“Y”/”N”), recorded recent accommodation status of alone/institution (“Y”/N”), psychiatric/cognitive risk factor count (“≤2”/”>2”), year HIV positive (“<2000”/”≥2000”) and duration weighted average CD4 cell count (“<500”/”≥500”/”Missing”). Record of suicidal ideation was excluded from model fitting because of collinearity associated with prior inclusion of psychiatric/cognitive risk factor count. The variables retained in the final model were average recent CD4 (p = 0.013), recent full time employment (p = 0.021), recent accommodation status of alone/institution (p = 0.005) and year HIV positive (p = 0.004) (Table 3).

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Table 3. Multivariate conditional logistic regression of determinants of suicide and accidental/violent death¹.

https://doi.org/10.1371/journal.pone.0089089.t003

Discussion

This study found multivariate association between increased risk of suicide and accidental or violent death in HIV-positive patients, psychosocial factors (employment and accommodation status) and recent immunological status while controlling for age, sex, mode of exposure, treating clinic and calendar year of HIV diagnosis.

We found an increased prevalence of observed psychosocial risk factors in cases which reflects well documented prognostic indicators [7], [19]. In particular, employment, accommodation status and suicidal ideation were associated with increased risk. In this study previously identified risk factors were not individually prognostic (alcohol intake, smoking status, recent recreational/illicit drug use, depression/anxiety, chronic pain and NCI). This is attributable to insufficient difference in prevalence between cases and controls for the given statistical power of this analysis. These results are also consistent with a high prevalence of psychosocial risk factors in HIV-positive populations in particular, but also in medically ill populations in general [20]–[23].

The observed significance of increased number of psychiatric/cognitive risk factors in analyses is consistent with the exacerbation of overall risk by cumulative burden of illnesses. Of recorded psychiatric/cognitive risk factors, only record of suicidal ideation was statistically significant, however, number of diagnoses of psychiatric/cognitive risk factors (≤2/>2 risk factors) was prognostic in univariate models. This variable may also more accurately reflect psychiatric/cognitive status by mitigating specific omissions or oversights as logged in and obtained from medical records.

This analysis found a recent CD4 cell count of ≥500 cells/µL to be a significant predictor of reduced risk of death by suicide, violence or accident. This remained significant in multivariate models after adjustment for socio-demographic factors (employment and accommodation status). The association of increased CD4 cell count and reduced risk has been demonstrated by Keiser et al [24], although that analysis did not adjust for other risk factors. Our study uses average recent CD4 cell count which reduces the influence of anomalous or non-characteristic measurements compared to single test values.

Models of suicide risk in HIV-positive populations generally incorporate complex causal pathways. In particular, psychosocial risk factors have been shown to predispose patients to non-adherence [25], [26] hence poorer HIV disease control. There are also reciprocal causal effects of immunological status on severity of neuropsychiatric symptoms as demonstrated by Warriner et al [27]. In our analysis there was no evidence of strong interaction between covariates, although robustness of multivariate models was limited by statistical power. In these models reduced level of immunological recovery can be seen to add to the overall risk associated with just psychosocial factors and may also indicate comorbidity effects specifically associated with HIV-disease.

We found earlier calendar year of HIV diagnosis to be associated with increased risk. This study only looks at post cART era mortality, when improved prognosis has been associated with some alleviation of psychosocial burden and reduced suicide risk [24]. However, increased all-cause mortality in HIV populations has been shown to be mainly attributable to risk factors identifiable prior to, or at early stages of cART [25]. While our results in part reflect increased experience of suboptimal therapy amongst high risk groups, they also suggest that extended duration of infection increases risk as has been observed in other chronic medical conditions [28].

Posited mechanisms for suicide risk in HIV-positive populations include the extent of neuro-protection and neuro-toxicity of ART although this was not supported by this analysis. In this study the recent use of neurocART was not significantly associated with risk in univariate analyses. Generally, there was no association between risk and neurocognitive impairment although increased observations are required to support these findings. Similarly, no specific antiretrovirals were associated with risk of suicide or death by violence or accident.

In this analysis all observed cases had reported mode of exposure as “MSM” or “MSM/IDU”. This reflects the composition of the AHOD cohort (>75% of exposures were via these modes) and of the wider epidemic in Australia, rather than necessarily the relative risk compared to other modes of exposure. In this study, cases and controls were matched on “MSM” or “MSM/IDU” mode of exposure and analyses therefore exclude confounding effects on risk arising from other modes of exposure in controls.

Generally, for case-control studies estimated relative risks are influenced by any causal association with case matching variables. Age, gender, MSM status and IDU history, which were categories used for case matching, have well documented association with the prevalence of general risk factors such as recent drug use, alcohol consumption, smoking status and psychiatric and cognitive risks. Given relatively low case numbers, this was an efficient way to conduct adjusted analyses of epidemic specific and less strongly associated predictors such as HIV related factors. Our results however, do not reflect risk associated with different categories of case matching variables.

This study has a number of limitations. First, primary analyses were based on suicide and accidental or violent death although correlates of accidental or violent death potentially differ from those of suicide only death. In this study, CoDe forms, which record detail of cause of death, facilitated the use of this endpoint to capture extra cases with likely similar associated risk behaviours. Specifically, eight of ten accidental or violent deaths were by overdose and the associated degree of intentionality could not be determined. While this may represent some loss of specificity, there is well documented association between drug use disorders and completed suicide [29]. Recently Bohnert et al have shown increased likelihood of US medical examiners to classify overdose deaths in cases with substance use disorders as indeterminate intent or unintentional compared to other psychiatric disorders and suggested that this might therefore indicate misclassification of suicide deaths for this group [30]. It is also possible that an additional proportion of accidental or violent deaths are in fact true suicide deaths but where official pronouncement of suicide might have been discouraged because of moral and legal implications [31]. Specifically in this analysis, deaths are very likely due to suicide or to have associated suicidal ideation. The increase in statistical power associated with the expanded endpoint has permitted more detailed analysis than possible by using suicide only death and should be considered in further analyses.

Second, there is a low absolute number of observed suicide deaths in AHOD. In this study we examined the expanded endpoint of suicide to include accidental or violent death and used efficient statistical methods including a case control design nested on certain accepted prognostic factors. However, results need to be carefully interpreted and the chance selection of non-associated variables in models cannot entirely be discounted. However, it is of interest that our findings are consistent with other analyses, as described [7], [19], [21]–[24].

Third, there may be site specific differences in comprehensiveness of reporting of certain risk factors. For example, certain treating centres restrict detailing of illicit drug use in patient records because of possible legal implications. Omitted data is not expected to introduce bias into analyses because of the case-control design of the study which matched cases and controls at the same treating centre.

In conclusion, immunological status of HIV-positive patients was found to add to the level of risk of suicide and accidental or violent death after adjustment for psychosocial factors. Number of psychiatric/cognitive diagnoses contributed to the level of risk but many psychosocial factors were not individually significant predictors of risk. These findings indicate a complex interplay of factors associated with risk of suicide and accidental or violent death.

Acknowledgments

Disclaimer: The views expressed in this publication do not necessarily represent the position of the Australian Government.

The members of the Australian HIV Observational Database are:

New South Wales: D Ellis, General Medical Practice, Coffs Harbour; M Bloch, T Franic*, S Agrawal, L McCann, N Cunningham, T Vincent, Holdsworth House General Practice, Darlinghurst; D Allen, JL Little, Holden Street Clinic, Gosford; D Smith, C Gray, Lismore Sexual Health & AIDS Services, Lismore; D Baker*, R Vale, East Sydney Doctors, Surry Hills; DJ Templeton*, CC O’Connor, C Dijanosic, RPA Sexual Health Clinic, Camperdown; E Jackson, K McCallum, Blue Mountains Sexual Health and HIV Clinic, Katoomba; M Grotowski, S Taylor, Tamworth Sexual Health Service, Tamworth; D Cooper, A Carr, F Lee, K Hesse, K Sinn, R Norris, St Vincent’s Hospital, Darlinghurst; R Finlayson, I Prone, Taylor Square Private Clinic, Darlinghurst; E Jackson, J Shakeshaft, Nepean Sexual Health and HIV Clinic, Penrith; K Brown, C McGrath, V McGrath, S Halligan, Illawarra Sexual Health Service, Warrawong; L Wray, P Read, H Lu, Sydney Sexual Health Centre, Sydney; D Couldwell, Parramatta Sexual Health Clinic; D Smith,V Furner, Albion Street Centre; Dubbo Sexual Health Centre, Dubbo; J Watson*, National Association of People living with HIV/AIDS; C Lawrence*, National Aboriginal Community Controlled Health Organisation; B Mulhall*, Department of Public Health and Community Medicine, University of Sydney; M Law*, K Petoumenos*, S Wright*, H McManus*, C Bendall*, M Boyd*, The Kirby Institute, University of NSW.

Northern Territory: A Kulatunga, P Knibbs, Communicable Disease Centre, Royal Darwin Hospital, Darwin.

Queensland: J Chuah*, M Ngieng, B Dickson, Gold Coast Sexual Health Clinic, Miami; D Russell, S Downing, Cairns Sexual Health Service, Cairns; D Sowden, J Broom, K Taing, C Johnston, K McGill, Clinic 87, Sunshine Coast-Wide Bay Health Service District, Nambour; D Orth, D Youds, Gladstone Road Medical Centre, Highgate Hill; M Kelly, A Gibson, H Magon, Brisbane Sexual Health and HIV Service, Brisbane.

South Australia: W Donohue,O’Brien Street General Practice, Adelaide.

Victoria: R Moore, S Edwards, R Liddle, P Locke, Northside Clinic, North Fitzroy; NJ Roth*, J Nicolson*, H Lau, Prahran Market Clinic, South Yarra; T Read, J Silvers*, W Zeng, Melbourne Sexual Health Centre, Melbourne; J Hoy*, K Watson*, M Bryant, S Price, The Alfred Hospital, Melbourne; I Woolley, M Giles, T Korman, J Williams, Monash Medical Centre, Clayton.

Western Australia: D Nolan, J Skett, J Robinson, Department of Clinical Immunology, Royal Perth Hospital, Perth.

Asterisks indicate steering committee members in 2011.

CoDe reviewers:

AHOD reviewers: D Sowden, DJ Templeton, J Hoy, L Wray, J Chuah, K Morwood, T Read, N Roth, I Woolley, M Kelly, J Broom.

TAHOD reviewers: PCK Li, MP Lee, S Vanar, S Faridah, A Kamarulzaman, JY Choi, B Vannary, R Ditangco, K Tsukada, SH Han, S Pujari, A Makane,, OT Ng, AJ Sasisopin.

Independent reviewers: F Drummond, M Boyd.