Causes of death in people living with HIV in the post 95 -95 -95 era: Lessons from five AIDS Healthcare Foundation clinics in Eswatini

doi:10.21203/rs.3.rs-4212331/v1

Background

Eswatini has a high HIV prevalence in adults (24.8%), and despite achieving HIV epidemic control, AIDS-related deaths are still high at 200 per 100,000 population. This study, therefore, describes the causes of death among people living with HIV (PLHIV) receiving care at five clinics in Eswatini.

Methods

Data of clients receiving antiretroviral therapy (ART) from five AIDS Healthcare Foundation (AHF) Clinics in Eswatini who died was analysed to describe the causes of death. Clients' records were included if they received treatment from any of the five clinics from January 1, 2021, to June 30, 2022. Clients' sociodemographic, clinical, and specific cause of death data were extracted from their clinical records into an Excel spreadsheet for mortality reporting and audits. The different causes of death were categorised and descriptive, and comparative analysis was done using Stata 15 and R. Odds ratio significant at p<0.05 (with 95% confidence interval) to estimate the different associations between the client's characteristics and the four leading causes of death.

Results

Of 257 clients, 52.5% (n=135) were males, and the median age was 47 years (IQR: 38, 59). The leading causes of death were non-communicable diseases (NCDs) (n=59, 23.0%), malignancies (n=37, 14.4%), Covid-19 (n=36, 14.0%) and advanced HIV disease (AHD) (n=24, 9.3%). Patients aged ≥60 years (OR 0.08; 95% CI: 0.004, 0.44) had lower odds of death from AHD than ≥40 years, and those who had been on ART for 12 – 60 months (OR 0.01; 95% CI: 0.0006, 0.06) and >60 months (OR 0.006; 95% CI: 0.0003, 0.029) had lower odds of death from AHD compared to those on ART for <12 months. Patients aged ≥40 years had higher odds of dying from COVID-19, while females (OR 2.64; 95% CI: 1.29, 5.70) had higher odds of death from malignancy.

Conclusion

Most patients who died were aged 40 years and above and died from an NCD, malignancy, COVID-19 and AHD-related cause. This indicates a need to expandprevention, screening, and integration of treatment for NCDs and cancers into HIV services. Specific interventions targeting younger PLHIV will limit their risks for AHD.

Human Immuno-Deficiency Virus

Advanced HIV Disease

People living with HIV

Antiretroviral therapy

Eswatini

Tuberculosis

Non-communicable disease

COVID-19

Malignancies

Cervical cancer

Global trends in AIDS-related mortality reveal the remarkable success of HIV care and prevention measures. HIV-related deaths have decreased from over two million in 2005 to 680,000 in 2020, representing 64% fewer deaths [1,2]. In developed countries, the annual number of deaths among people living with HIV (PLHIV) has fallen substantially, and modelling suggests that the life expectancy of PLHIV is approaching that of the general population [3]. While the life expectancy of adults with HIV may be near that of those without HIV, evidence suggests the need for greater attention to be paid to preventing comorbidities which have contributed towards persistently higher mortality [4]. A study in the United States of America of over 40,000 adults living with HIV with matched HIV-negative controls showed that individuals living with HIV lived 6.8 fewer years overall and had 9.5 more years with significant co-morbidities even after ART initiation at high CD4 counts [4]. Long-term HIV infection is associated with degenerative co-morbidities caused by persistent, low-grade immune activation, inflammation, and hypercoagulability despite suppressive antiretroviral therapy (ART) [5]. Ageing with HIV presents a new set of challenges due to a combination of age-associated degenerative diseases and the co-morbidities associated with HIV infection [5].

In Africa, HIV/AIDS-related deaths have fallen by more than half, from over 1 million in 2000 to 435,000 in 2019, primarily due to the introduction of highly effective ART [2]. HIV-AIDS as a cause of death has dropped from first to fourth position between 2000 and 2019 [6]. However, in Sub-Saharan Africa, home to more than two-thirds of the world's HIV-positive population, HIV remains a public health threat [7]. Studies in Sub-Saharan Africa have shown that although other countries still report a high incidence of AIDS-related deaths, there is a shift in the predominant causes of death from AIDS-related to non-AIDS-defining conditions [8–10].

Eswatini has the highest global prevalence of HIV at 24.8% in people aged 15 years and above, with an estimated 220,000 PLHIV as of 2022 [1,11]. The country is an early adopter of evidence-based HIV control interventions, having introduced and scaled up a national ART Program in 2004 and started implementing universal treatment for all in 2016. This has contributed to a 50% decline in HIV-related mortality between 2010 and 2016 [12,13]. As of 2019, AIDS-related deaths in Eswatini had dropped to 200 per 100,000 population from 400 per 100,000 in 2010 [14], and current projections indicate a continued reduction in mortality [15]. Eswatini is one of the first countries to achieve the UNAIDS 95-95-95 targets alongside Switzerland and is on track to achieve HIV epidemic control [16,17].

With the achievement of the UNAIDS 95-95-95 targets [16,18], there is a need for the HIV care and treatment program in Eswatini to focus on providing a better quality of life for PLHIV by addressing the prevalent causes of morbidity and mortality. To understand the causes of mortality in this population with high ART coverage and Viral Load (VL) suppression rates, the study aims to describe the specific causes of death amongst PLHIV on treatment at five AIDS Healthcare Foundation (AHF)-Eswatini clinics from January 2021 to June 2022.

Study setting and population

This study was conducted at five fully AHF-supported HIV clinics located in three of Eswatini's four regions: AHF Lamvelase Help Centre and AHF Matsapha, both in the Manzini region; AHF Mbabane in the Hhohho region; AHF Nhlangano in the Shiselweni region; and AHF Piggs Peak in the Hhohho region. AHF commenced services in 2007 in Eswatini and currently serves about 31,300 PLHIV receiving HIV care and treatment in Eswatini as of December 2021.

The study population included PLHIV of all ages and genders enrolled at the five health facilities, regardless of ART status (on ART or pre-ART) and receiving care at an AHF site at the time of death. Individuals qualified for inclusion in this study only if they had been actively receiving HIV care at any of the five AIDS Healthcare Foundation facilities in Eswatini and became deceased, with their death being officially recorded in the period from January 1, 2021, to June 30, 2022. Individuals were excluded if their deaths were reported before or after the study period. Formal sample size analysis and sampling were not required for this study.

Study design and data management

A cross-sectional analysis of mortality data was conducted from the clinics' electronic database (Antiretroviral Therapy Patient Monitoring and Reporting – APMR), patients' files and records of PLHIV who were receiving HIV care and whose death was reported between January 2021 and June 2022.

Data were extracted from the APMR and patients' chronic care files into an Excel spreadsheet (Supplementary file 1) for mortality reporting and audit. The APMR system collects mandatory data related to routine patient monitoring, clinical treatment, and outcomes, and mortality data are routinely reported and audited in an Excel spreadsheet. The causes of death are determined from death certificates, declarations, and a combination of information from verbal autopsies (family members or friends), the last morbid conditions, or health information in the medical records. A clinician, generally the senior medical officer or the senior nurse, must confirm the cause of death during routine mortality audits. All mortality data collected at different sites are submitted and validated by the AHF country medical manager. Death is reported as unknown when all the above sources are not informative. Advanced HIV disease was attributed to PLHIV, whose CD4+ cell count was less than 100 μl/l at the time of their death and/or if they were reported to have died with WHO stage 3 or 4 conditions.

The Excel spreadsheets used for data collection are standardised across all AHF sites in Eswatini. They include the clinic ID (file number), gender, age at the time of death, date of HIV test, date of death (or of notification if the date of death is unknown), WHO stage, functional status at the time of death, ART status, duration in care, duration on ART, initial CD4, last CD4, date of last visit, cause or condition at death, HIV regimen, last VL, and last clinician who attended the patient (nurse or Doctor). The initial CD4 is the CD4 at ART initiation, and the last CD4 is the last available CD4 in the client's records.

As of 2018, clients stable on ART with undetectable viral load and CD4 count ≥ 350 cells/mm3 were no longer required to undergo routine CD4 count monitoring [19], indicating that the last CD4 could have been documented several years before the client's demise. The last VL was only considered if taken within the 12 months before the client's previous visit. However, based on the 2018 Eswatini Integrated HIV Management guidelines, clients were only eligible for VL 6 months after ART initiation. Therefore, all clients without VL in the first six months of ART initiation were labelled "Not Eligible".

Using a programmatic approach, two clinicians assigned the reasons for death in 9 different categories. The categories are Accident/Assault, Advanced HIV Disease (AHD) conditions, COVID-19, Malignancy, Non-Communicable diseases (NCDs), Organ failure, Suicide, Tuberculosis, Others, and Unknown. In the absence of a CD4 and WHO 3 or 4 conditions or any other cause of death, clients were considered to have died of an AHD if they were enrolled in care within six months before their death, which coincided with a positive HIV test or ART initiation. Clients deceased with tuberculosis were grouped separately even if co-morbidities or CD4 level would have classified them otherwise (e.g., AHD); we used the same approach for COVID-19. All other causes of death that were in too small numbers to constitute a category were grouped as "Others". Functional status was defined as working, when the patient can carry out regular work in or outside the home, harvest crops, attend school, or, for children, engage in everyday activities or play; ambulatory, when the patient can carry out daily activities but unable to work or play; or bedridden, when the patient is unable to carry out daily activities [20,21].

Ethics Statement

The study protocol was submitted to the Eswatini Health and Human Research Review Board (EHHRRB) for ethical review and approval. Since this study utilised deceased patients' records without their physical presence, informed consent was not obtained, and EHHRRB waived this requirement.

Statistical methods

The data was initially checked for accuracy, consistency, and completeness. Where discrepancies were observed, the data was verified with the original patient record to ensure accuracy and completeness. A descriptive analysis of clinical and sociodemographic characteristics was performed; categorical descriptors were presented as numbers with proportions, while numeric descriptors were presented as a mean with standard deviations (SD) or median with interquartile range (IQR). The different causes of death were identified and grouped to identify the overall and cause-specific causes. The cause-specific mortality rates were determined as the number of each specific cause of death and expressed as a proportion of the total number of deceased patients. This was presented using a table and a chart based on the deceased's clinical and sociodemographic features.

A comparative analysis using Pearson χ2 or Fischer's exact test for categorical variables, T-test or Mann-Whitney test for continuous variables to identify associations between causes of death and clinical and sociodemographic characteristics of the deceased. Bivariate regression analysis used R code for variables that showed a statistical difference during the comparative analysis. The odd ratio was estimated to compare different categories. Statistical significance was set at p<0.05, with a 95% confidence interval (95% CI). Stata version 15 (College Station, TX) was used for statistical analysis.

Sociodemographic and clinical characteristics of deceased patients

Patients whose deaths were reported between January 2021 and June 2022 were included in the study (n=257). Table 1 summarises the key characteristics of these patients. Almost half (n=124, 48.2%) of the patients were seen at the Lamvelase clinic, 52.5% (n=135) were males, and the median age of all the patients was 47 years (IQR 38, 59). The majority who died (n=240, 92.6%) were aged ≥30 years, with more deaths in the 40-49 (n=67, 26%) and ≥60 (n=63, 24.6%) years age group. The median baseline CD4 count for all patients was 177.5 (IQR 71, 315), while the last CD4 count before death was 418.5 (IQR 255, 596) and based on the last documented viral load result, about 80% of the patients (n=205) had a suppressed viral load. Most patients at the time of death (n=251, 97.7%) had commenced ART, and 82.5% were on a Dolutegravir-based ART regimen. The median duration of ART was 78 months (IQR 29, 120), and 16% (n=40) had received ART for less than twelve months at the time of death.

Table 1: Characteristics of deceased patients

Variable	Female (N=122)	Male (N=135)	Total (N=257)
Clinic
Lamvelase	68 (55.7%)	56 (41.5%)	124 (48.2%)
Matsapha	30 (24.6%)	29 (21.5%)	59 (23.0%)
Mbabane	8 (6.6%)	17 (12.6%)	25 (9.7%)
Nhlangano	15 (12.3%)	30 (22.2%)	45 (17.5%)
Pigg's Peak	1 (0.8%)	3 (2.2%)	4 (1.6%)
Age			124 (48.2%)
≤ 19	0 (0.0%)	2 (1.5%)	2 (0.8%)
20-29	11 (9.0%)	6 (4.4%)	17 (6.6%)
30-39	29 (23.8%)	25 (18.5%)	54 (21.0%)
40-49	29 (23.8%)	38 (28.2%)	67 (26.0%)
50-59	30 (24.6%)	24 (17.8%)	54 (21.0%)
≥ 60	23 (18.8%)	40 (29.6%)	63 (24.6%)
Mean (SD)	47.25 (13.71)	49.70 (14.04)	48.54 (13.91)
Median (Q1, Q3)	47.0 (37.0, 56.5)	48.5 (40.0, 61.0)	47.0 (38.0, 59.0)
Functional status
Ambulatory	16 (13.1%)	27 (20.0%)	43 (16.7%)
Bedridden	9 (7.4%)	4 (3.0%)	13 (5.1%)
Walking	97 (79.5%)	104 (77.0%)	201 (78.2%)
Baseline CD4
<100	29 (23.8%)	42 (31.1%)	71 (27.6%)
100-199	25 (20.5%)	22 (16.3%)	47 (18.3%)
200-349	23 (18.9%)	32 (23.7%)	55 (21.4%)
>=350	22 (18.0%)	21 (15.6%)	43 (16.7%)
Not available	23 (18.8%)	18 (13.3%)	41 (16.0%)
Mean (SD)	234.5 (246.8)	231.6 (246.5)	232.0 (246.0)
Median (Q1, Q3)	178.0 (75.0, 316.0)	177.0 (70.0, 315.5)	177.5 (71.0, 315.3)
Last CD4
<100	10 (8.2%)	10 (7.4%)	20 (7.8%)
100-199	6 (4.9%)	13 (9.6%)	19 (7.4%)
200-349	19 (15.6%)	17 (12.6%)	36 (14.0%)
>=350	71 (58.2%)	64 (47.4%)	135 (52.5%)
Not available	16 (13.1%)	31 (23.0%)	47 (18.3%)
Mean (SD)	464.1 (294.9)	460.4 (295.8)	460.4(295.1)
Median (Q1, Q3)	419.0 (257.5, 598.5)	418.0 (254.0, 598.0)	418.5 (254.6, 596.0)
ART (Y/N)
No	3 (2.5%)	3 (2.2%)	6 (2.3%)
Yes	119 (97.5%)	132 (97.8%)	251 (97.7%)
REGIMEN
ABC/3TC/DTG	11 (9.0%)	12 (8.9%)	23 (8.9%)
ABC/3TC/EFV	1 (0.8%)	2 (1.5%)	3 (1.2%)
ABC/3TC/LPVr	0 (0.0%)	1 (0.7%)	1 (0.4%)
AZT/3TC/DTG	5 (4.1%)	7 (5.2%)	12 (4.7%)
AZT/3TC/EFV	1 (0.8%)	0 (0.0%)	1 (0.4%)
TDF/3TC/DTG	74 (60.7%)	103 (76.3%)	177 (68.9%)
TDF/3TC/EFV	27 (22.1%)	7 (5.2%)	34 (13.2%)
Not on ART	3 (2.5%)	3 (2.2%)	6 (2.3%)
Latest VL Category
No VL	4 (3.3%)	6 (4.4%)	10 (3.9%)
Not Eligible	16 (13.1%)	20 (14.8%)	36 (14.0%)
Not Suppressed	3 (2.5%)	3 (2.2%)	6 (2.3%)
Suppressed	99 (81.1%)	106 (78.6%)	205 (79.8%)
Duration On ART (Months)
<12 Months	16 (13.1%)	24 (17.8%)	40 (15.6%)
12-60 Months	33 (27.0%)	37 (27.4%)	70 (27.2%)
61-120 Months	39 (32.0%)	49 (36.3%)	88 (34.2%)
>120 Months	34 (27.9%)	25 (18.5%)	59 (23.0%)
Mean (SD)	84.5 (56.7)	73.1 (55.1)	78.5 (56.1)
Median (Q1, Q3)	88.0 (37.0, 127.0)	71.0 (24.0, 115.0)	78.0 (29.0, 120.0)
Last seen by
Doctor	34 (27.9%)	31 (23.0%)	65 (25.3%)
Nurse	79 (64.7%)	89 (65.9%)	168 (65.4%)
Unknown	9 (7.4%)	15 (11.1%)	24 (9.3%)

Specific causes of death

Table 2 and Supplementary File 2 summarise the specific causes of death (n=209), excluding those with an unknown cause of death (n=48). The leading causes of death were non-communicable diseases (NCDs) (n=59, 23.0%), malignancies (n=37, 14.4%), Covid-19 (n=36, 14.0%) and AHD (n=24, 9.3%). Of the 257, only 7.0% (n=18) died from Accident/Assault, 4.3% (n=11) from organ failure, 2.7% (N=7) from tuberculosis, and 2.3% (N=6) from suicide. Forty-eight (18.7%) had an unknown cause of death. Most who died were from the Lamvelase clinic, mostly from NCD (n=29), malignancy (n=20) and COVID-19 (n=14).

Non-communicable diseases (NCD)

Most patients who died from an NCD (n=54, 91.5%) were from the Lamvelase, Matsapha and Nhlangano clinics. The most reported NCD causes of death were cardiovascular diseases (including hypertension and stroke) (n=18), chronic kidney disease (n=15), chronic anaemia of unknown cause (n=6) and diabetes (n=5). More NCD-related deaths (n=32, 54%) occurred in females, and while all age groups contributed to NCD deaths, the majority were ≥30 years old (n=55, 93%), mainly with WHO stages 1 and 2 HIV disease (n=43, 72.8%), and most (n=54, 91.5%) had been on ART for ≥12 months.

Malignancy

The most reported malignancies were that of the cervix and urogenitalia (n=8), prostate and penile tissue (n=4), skin and soft tissues (n=4), breast (n=3) and eye (n=2). More females died from malignancies (n=25, 67%) compared to males and the majority who died were aged ≥40 years (n=30, 81%).

COVID-19

More males died from COVID-19-related deaths, and the majority of those who died (n=33, 92%) were aged ≥40 years old. Twenty-nine (80.5%) were classified as WHO stage 1 and 2, and similar numbers across the different baseline CD4 groups. The majority who died from COVID-19 had been on ART for ≥12 months (n=33, 92%) and with a walking functional status (n=33, 92%).

Advanced HIV Disease

Most patients who died from AHD were from the Nhlangano clinic (n=11, 46%), and the majority who died were males (n=15, 62.5%), mostly aged ≥30 years old (n=22, 92%). Most clients who died from AHD (n=20, 83%) were classified as WHO stage 3 and 4, with more than half (n=13, 54%) presenting with a baseline CD4<100 cells/ml and 92% (n=22) on ART for less than 12 months.

Table 2: Description of specific causes of death by patient's demographic and clinical characteristics

Characteristic	Cause of Death									Total
Characteristic	AHD	Assault/Accident	COVID-19	Malignancy	NCD	Organ failure	Others	Suicide	Tuberculosis	Total
	(N = 24)	(N = 18)	(N = 36)	(N = 37)	(N = 59)	(N = 11)	(N = 11)	(N = 6)	(N = 7)	(N = 209)
Clinic
Lamvelase	6 (25.0%)	7 (38.9%)	14 (38.9%)	20 (54.1%)	29 (49.2%)	3 (27.3%)	6 (54.5%)	3 (50.0%)	3 (42.9%)	124 (48.2%)
Matsapha	4 (16.7%)	3 (16.7%)	9 (25.0%)	9 (24.3%)	15 (25.4%)	6 (54.5%)	4 (36.4%)	2 (33.3%)	2 (28.6%)	59 (23.0%)
Mbabane	3 (12.5%)	2 (11.1%)	7 (19.4%)	6 (16.2%)	5 (8.5%)	0 (0.0%)	1 (9.1%)	0 (0.0%)	1 (14.3%)	25 (9.7%)
Nhlangano	11 (45.8%)	5 (27.8%)	6 (16.7%)	2 (5.4%)	10 (16.9%)	0 (0.0%)	0 (0.0%)	1 (16.7%)	0 (0.0%)	45 (17.5%)
Pigg's Peak	0 (0.0%)	1 (5.6%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	2 (18.2%)	0 (0.0%)	0 (0.0%)	1 (14.3%)	4 (1.6%)
Gender
Female	9 (37.5%)	6 (33.3%)	14 (38.9%)	25 (67.6%)	32 (54.2%)	4 (36.4%)	5 (45.5%)	3 (50.0%)	4 (57.1%)	122 (47.5%)
Male	15 (62.5%)	12 (66.7%)	22 (61.1%)	12 (32.4%)	27 (45.8%)	7 (63.6%)	6 (54.5%)	3 (50.0%)	3 (42.9%)	135 (52.5%)
Age Category
<19	1 (4.2%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (1.7%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	2 (0.8%)
20-29	1 (4.2%)	3 (16.7%)	1 (2.8%)	0 (0.0%)	3 (5.1%)	0 (0.0%)	0 (0.0%)	3 (50.0%)	1 (14.3%)	17 (6.6%)
30-39	10 (41.7%)	5 (27.8%)	2 (5.6%)	7 (18.9%)	13 (22.0%)	3 (27.3%)	6 (54.5%)	2 (33.3%)	1 (14.3%)	54 (21.0%)
40-49	7 (29.2%)	5 (27.8%)	13 (36.1%)	13 (35.1%)	7 (11.9%)	3 (27.3%)	2 (18.2%)	1 (16.7%)	1 (14.3%)	67 (26.1%)
50-59	4 (16.7%)	3 (16.7%)	11 (30.6%)	8 (21.6%)	17 (28.8%)	2 (18.2%)	0 (0.0%)	0 (0.0%)	2 (28.6%)	54 (21.0%)
=>60	1 (4.2%)	2 (11.1%)	9 (25.0%)	9 (24.3%)	18 (30.5%)	3 (27.3%)	3 (27.3%)	0 (0.0%)	2 (28.6%)	63 (24.5%)
WHO Stage
1	3 (12.5%)	13 (72.2%)	22 (61.1%)	20 (54.1%)	32 (54.2%)	7 (63.6%)	8 (72.7%)	5 (83.3%)	2 (28.6%)	137 (53.3%)
2	1 (4.2%)	1 (5.6%)	7 (19.4%)	7 (18.9%)	11 (18.6%)	2 (18.2%)	1 (9.1%)	1 (16.7%)	0 (0.0%)	43 (16.7%)
3	6 (25.0%)	4 (22.2%)	5 (13.9%)	2 (5.4%)	5 (8.5%)	1 (9.1%)	2 (18.2%)	0 (0.0%)	4 (57.1%)	37 (14.4%)
4	14 (58.3%)	0 (0.0%)	2 (5.6%)	8 (21.6%)	11 (18.6%)	1 (9.1%)	0 (0.0%)	0 (0.0%)	1 (14.3%)	40 (15.6%)
Baseline CD4
<100	13 (54.2%)	3 (16.7%)	7 (19.4%)	8 (21.6%)	15 (25.4%)	5 (45.5%)	2 (18.2%)	1 (16.7%)	3 (42.9%)	71 (27.6%)
100-199	1 (4.2%)	3 (16.7%)	9 (25.0%)	7 (18.9%)	11 (18.6%)	3 (27.3%)	1 (9.1%)	0 (0.0%)	0 (0.0%)	47 (18.3%)
200-349	0 (0.0%)	5 (27.8%)	8 (22.2%)	8 (21.6%)	17 (28.8%)	0 (0.0%)	4 (36.4%)	2 (33.3%)	1 (14.3%)	55 (21.4%)
>=350	0 (0.0%)	5 (27.8%)	3 (8.3%)	8 (21.6%)	9 (15.3%)	2 (18.2%)	2 (18.2%)	2 (33.3%)	2 (28.6%)	43 (16.7%)
Not available	10 (41.7%)	2 (11.1%)	9 (25.0%)	6 (16.2%)	7 (11.9%)	1 (9.1%)	2 (18.2%)	1 (16.7%)	1 (14.3%)	41 (16.0%)
ART Duration
<12 Months	22 (91.7%)	1 (5.6%)	3 (8.3%)	0 (0.0%)	5 (8.5%)	1 (9.1%)	0 (0.0%)	0 (0.0%)	2 (28.6%)	40 (15.6%)
12-60 Months	1 (4.2%)	10 (55.6%)	15 (41.7%)	11 (29.7%)	13 (22.0%)	3 (27.3%)	2 (18.2%)	5 (83.3%)	1 (14.3%)	70 (27.2%)
61-120 Months	1 (4.2%)	4 (22.2%)	7 (19.4%)	13 (35.1%)	30 (50.8%)	6 (54.5%)	4 (36.4%)	0 (0.0%)	3 (42.9%)	88 (34.2%)
>120 Months	0 (0.0%)	3 (16.7%)	11 (30.6%)	13 (35.1%)	11 (18.6%)	1 (9.1%)	5 (45.5%)	1 (16.7%)	1 (14.3%)	59 (23.0%)
Functional status
Ambulatory	9 (37.5%)	1 (5.6%)	3 (8.3%)	9 (24.3%)	9 (15.3%)	2 (18.2%)	0 (0.0%)	2 (33.3%)	5 (71.4%)	43 (16.7%)
Bedridden	2 (8.3%)	2 (11.1%)	0 (0.0%)	2 (5.4%)	5 (8.5%)	1 (9.1%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	13 (5.1%)
Walking	13 (54.2%)	15 (83.3%)	33 (91.7%)	26 (70.3%)	45 (76.3%)	8 (72.7%)	11 (100.0%)	4 (66.7%)	2 (28.6%)	201 (78.2%)

Assault/Accident-related deaths

All clinics had a patient who died from assault/accident, and the majority were from the Lamvelase (n=7, 38%) and Nhlangano clinics (n=5, 28%). More males (n=12, 67%) died from assault/accident compared to females, with similar distribution across age groups, most from the age group 30 – 49 years (n=10, 55.6%). 72% were classified as WHO stage 1 with a similar number of deaths across the different baseline CD4 groups, more than half receiving ART for 12 – 60 months; 83% (n=15) with a walking functional status.

Organ failure, Suicide, Tuberculosis and Other causes of death

Organ failure was similar between the sexes and across all age groups after age 29. The majority had been on ART for ≥12 months (n=10, 91%), and 72% (n=8) had a walking functional status. Most of those who died from suicide were from the Lamvelase and Matsapha clinics (n=5, 83%), and half were between 20 – 29 years. They were all in WHO stages 1 and 2 and mostly on ART for 12 – 60 months (n=5, 83%). Those who died from tuberculosis were mainly from the Lamvelase and Matsapha clinics, similar across both sexes, and most (n=5, 71%) were classified as WHO stage 3 and 4 with varied baseline CD4 and mostly ambulatory functional status (n=5, 71%). Causes of death classified as "Other" include pneumonia (with similar chest symptoms) (n=6), acute gastroenteritis (n=2), sudden collapse (n=2) and meningitis (n=1).

Comparison of deceased characteristics and the four causes of death

Table 3 describes the bivariate analysis of the different associations between the patient's sociodemographic and clinical characteristics and the four leading causes of death. Compared to patients younger than 40, older patients were less likely to die from AHD, which was statistically significant for those aged ≥60 years old (OR 0.08; 95% CI: 0.004, 0.44). Similarly, patients who had been on ART for 12 – 60 months (OR 0.01; 95% CI: 0.0006, 0.06) and >60 months (OR 0.006; 95% CI: 0.0003, 0.029) had lower odds of death due to AHD compared to those on ART for less than 12 months. Patients with ambulatory functional status (OR 3.83; 95% CI 1.48-9.60) had higher odds of death from AHD than those with a walking functional status.

Patients aged 40-49 years (OR 5.62; 95% CI: 1.7, 25.4), 50-59 years (OR 5.97; 95% CI: 1.8, 27.5) and ≥60 years (OR 3.89; 95% CI: 1.10, 18.16) had higher odds of dying from a COVID-19-related complication compared to those aged <40 years old. Females had lower odds of death from a COVID-19-related complication, but this was not statistically significant. Females (OR 2.64; 95% CI: 1.29, 5.70) had higher odds of death from a malignancy-related cause than males. For NCDs, the age group 40-49 years (OR 0.38; 95% CI: 0.14, 0.96) had lower odds of death compared to those younger than 40 years, while those on ART for >60 months (OR 2.70; 95% CI: 1.07, 8.31) had higher odds of death due to an NCD compared to those on ART for <12 months.

Table 3: Bivariate analysis of the effect of the different patient characteristics on the top four causes of death

Characteristic		AHD OR (95%CI)	COVID-19 OR (95%CI)	Malignancy OR (95%CI)	NCD OR (95%CI)
Sex	Male	Ref	Ref	Ref	Ref
Sex	Female	0.63 (0.26, 1.49)	0.67 (0.32, 1.36)	2.64 (1.29, 5.7)	1.42 (0.79, 2.56)
Age	<40	Ref	Ref	Ref	Ref
	40-49	0.59 (0.21, 1.58)	5.62 (1.71, 25.40)	2.27 (0.87, 6.41)	0.38 (0.14, 0.96)
	50-59	0.41 (0.11, 1.25)	5.97 (1.75, 27.49)	1.64 (0.55 4.98)	1.51 (0.68, 3.35)
	≥60	0.08 (0.004, 0.44)	3.89 (1.10, 18.16)	1.57 (0.55, 4.66)	1.31 (0.61, 2.87)
ART Duration	< 12 months	Ref	Ref	Ref	Ref
	12 – 60 months	0.01 (0.0006, 0.06)	3.36 (1.02, 15.25)	> 10 (overlaps 1)	1.59 (0.55, 5.32)
	> 60 months	0.006 (0.0003, 0.029)	1.72 (0.54, 7.63)	> 10 (overlaps 1)	2.70 (1.07, 8.31)
Baseline CD4	<200 (Ref)	Ref	Ref	Ref	Ref
	≥200	<0.001 (overlaps 1)	0.81 (0.35, 1.81)	1.34 (0.62, 2.89)	1.28 (0.68, 2.39)
	Not available	2.40 (0.95, 5.90)	1.79 (0.70, 4.38)	1.18 (0.39, 3.15)	0.73 (0.27, 1.76)
Last CD4	< 200	Ref	Ref	Ref	Ref
	≥200	< 0.001 (overlaps 1)	0.94 (0.38, 2.70)	1.71 (0.62. 6.06)	1.63 (0.71, 4.26)
	Unavailable	2.0 (0.76, 5.56)	0.65 (0.17-2.36)	1.04 (0.26, 4.49)	0.8 (0.25, 2.56)
Last VL	Not Suppressed	Ref	-	Ref	Ref
	Suppressed	<0.001 (overlaps 1)	-	1.03 (0.16, 20.0)	1.66 (0.26, 32.1)
	Not eligible	2.24 (0.39, 1.76)	-	<0.001 (Overlaps 1)	0.63 (0.71, 13.5)
ART	No (Ref)	Ref	Ref	Ref	Ref
ART	Yes	0.07 (0.01, 0.31)	-	> 10 (Overlaps 1)	-
Functional status	Walking (Ref)	Ref	Ref	Ref	Ref
	Bedridden	2.63 (0.38, 11.2)	<0.001 (Overlaps 1)	1.22 (0.18, 4.90)	2.17 (0.63, 6.82)
	Ambulatory	3.83 (1.48, 9.60)	0.38 (0.09, 1.14)	1.58 (0.73, 4.03)	0.92 (0.39, 1.99)

We aimed to describe the specific causes of death amongst PLHIV on treatment at five AIDS Healthcare Foundation (AHF)-Eswatini clinics from January 2021 to June 2022 and to determine if there are differences in the causes of death based on patient characteristics. Non-communicable diseases (NCDs), malignancies, Covid-19 and AHD were the leading causes of death. More than half who died were males, and most patients were aged ≥40 years. NCD-related deaths increased with the age and duration of ART. The odds of dying from COVID-19-related complications were higher for those aged ≥40 years, and more females died from malignancy-related causes than males. Older patients were less likely to die from AHD, and those on ART for less than 12 months were more likely to die from AHD.

Our finding of non-communicable diseases as the leading cause of death amongst PLHIV is not surprising. Earlier studies from Tanzania, Zimbabwe and Uganda, while observing the traditional infectious disease causes of death, such as tuberculosis, AIDS-related opportunistic infections and malignancies, observed increasing trends in non-communicable disease as a cause of death from 2015 [8,9,22–24]. Cardiovascular diseases (hypertension, stroke), kidney diseases, diabetes mellitus and malignancies have been identified as the most common NCD causes of death from these earlier studies [8,9,22]. Additionally, those who died from NCDs were observed to be much older, above 40 years [23,25]. Our analysis identified NCDs as the leading cause of mortality, confirming that these trends have progressed.

Unlike studies conducted before 2018 in Burkina Faso, Uganda, Ghana, and South Africa [23,24,26,27], tuberculosis was not among our cohort's top three causes of death. This could be attributed to the fact people with HIV now access more effective medication with improved immune response against opportunistic infections and are living to older ages common with NCDs [28,29]. For instance, 80% of patients in our cohort had a suppressed last viral load, and 71% were ≥40 years old, an age commonly associated with NCDs. In addition to the above, HIV-TB coinfection has dropped over the years in Eswatini. It can also be attributed to the high coverage of TB prophylactic treatment amongst PLHIV in Eswatini [30].

The observed deaths from malignancies in our cohort, mainly amongst females from genital cancers, indicate a limited availability of cancer prevention, screening, and treatment services within the HIV program in Eswatini. For instance, HPV vaccines have only been recently rolled out and are not widely accessible, and few eligible women living with HIV have access to cervical screening and treatment services, as this is offered in only 37% of health facilities [31,32]. Previously, most PLHIV who died from malignancies were from non-Hodgkin lymphoma and Kaposi Sarcoma [33]. Few males, however, still die of a malignant condition which may not directly be related to HIV, but due to the limited availability of screening and treatment programs to aid early diagnosis, treatment, and follow-up.

Death from COVID-19-related complications ranked high in our list of causes of death – not surprising as data from our cohort was obtained at the peak of the COVID-19 pandemic. Evidence suggests most COVID-19-related deaths occurred in people aged ≥40 years [34], with an increased risk of death in those with comorbid conditions, including hypertension, diabetes, renal diseases, and malignancies and patients undergoing dialysis [34]. Given that most of our patients who died had an NCD and were older than 40 years, we believe they were also at risk of COVID-19 and could have also had COVID-19-related complications.

Contrary to earlier studies in Tanzania and Zimbabwe, where ≥50% of HIV-related deaths occurred within the first year of commencing ART and from acute causes [8,9], most of our patients survived the first year of treatment, with only 15% dying within the first twelve months of treatment and 57% after 60 months of treatment indicating patients are more stable at diagnosis. The causes of death have shifted from acute to more chronic conditions. From three earlier studies from Sierra Leone [35], Ghana [26] and five West African countries [24], more deaths were from AHD amongst bedridden in-patients, usually within the first week of admission, primarily due to anaemia, diarrheal disease, cerebral toxoplasmosis or tuberculosis [24,26,35]. This is different from our study, as only 5% of patients who died were bedridden, with older adults (≥40 years) having lower odds of dying from AHD. This observed difference could be due to changes in treatment guidelines, e.g., test-and-treat [36], where patients commence treatment immediately after a positive diagnosis instead of depending on the CD4 count, which made a lot of patients present late with AHD [3,37]; the introduction of a more potent antiretroviral therapy such as Dolutegravir and the scale-up of HIV prevention, testing and treatment services in high burden countries and amongst different sub-population groups.

Strength and limitations

Given the widespread use of ART in Eswatini and the achievement of HIV epidemic control, this study contributes to the literature on the possible causes of death in a mature HIV program. This will guide other programs to institute adequate preventive measures when scaling up HIV services. Secondly, data for this study was obtained during the COVID-19 pandemic, which enabled us to explore the associations between different patient characteristics and COVID-19 as a cause of death. On the contrary, our study has some limitations. First, we used data from health facility records to determine the cause of death without forensics, comprehensive autopsy reports or, at a minimum, verbal autopsy. Some causes of death may have been incorrectly assigned, especially for those who died at home. It was determined that the client's most recent documented condition was the cause of death when there was no identifiable cause of death. A unified vital records system for reporting and documenting deaths is yet to be rolled out in Eswatini, and our approach provided an approximate method for describing the cause of death. Secondly, service delivery during the pandemic was variable and could have limited services received by a patient. Third, we could not identify the cause of death for some patients, and mortality might have been underestimated due to unreported deaths among unreachable clients reported as lost to follow-up (LTFU). This could have biased our estimates for the causes of death. Despite these limitations, we believe some key learnings from this study will be helpful to different cadres of healthcare workers and HIV program implementers.

As most of our patients were ≥40 years old and died from an NCD, the integration of NCD screening and treatment services into infectious disease programs, as recommended by the World Health Organization [38], will help identify ART clients at risk of complications and death for improved care. More women observed to have died from malignancies could have been avoided if HPV vaccines were widely accessible and cancer screening and treatment services for HIV-positive clients were available, particularly cervical cancer screening and treatment for eligible women and prostate cancer screening and treatment for males. Context-specific interventions targeting males and middle-aged people (ages 30-39) aimed at early diagnoses and treatment can further limit the presentation with AHD and death in middle-aged people. Finally, the rollout of an effective vital records registration system for deaths will help track the number, trends and causes of death in the general population and amongst ART clients across multiple patient databases and through records linkage.

AHD	Advanced HIV Disease
AHF	AIDS Healthcare Foundation
ART	Antiretroviral Therapy
CD4+	Cluster of Differentiation 4
COVID-19	Corona Virus Disease 2019
EHHRRB	Eswatini Health and Human Research Review Board
HIV	Human Immunodeficiency Virus
HPV	Human Papilloma Virus
NCD	Non-Communicable Disease
PLHIV	People Living with HIVJ
UNAIDS	Joint United Nations AIDS Program
VL	Viral Load
WHO	World Health Organization

Acknowledgement

We thank the healthcare workers who assisted with patient care and data collection and the patient relatives for providing some details that helped clarify the cause of death.

Authors contributions

Conceptualisation: YM, SK, VW, ND, SH. Patient care and documentation: YM, SK, EN, NN, KM, HS, SG, NM, ND, LB, ND. Data extraction: SN, KM, HS, SG. Data analysis: YM, VW, SN, AK, AM. First draft: YM, VW, SK. Review of first draft: EN, NN, AK, NM, AM, PB, ND, LB, ND, SH. Ethical clearance: YM, SK. Review and approval of final draft: All authors.

Funding

The write-up of this research did not receive any specific funding. The AIDS Healthcare Foundation (AHF) LaMvelase Clinic, Manzini, Eswatini receives technical assistance from the Support Eswatini Achieve and Sustain HIV Epidemic Control (SEASEC) Program funded by the US President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) (Co-operative Agreement No.:NU2GGH002294), implemented by Georgetown University in collaboration with the Government of the Kingdom of Eswatini. Alexander Kay’s training award was granted by the National Institutes of Health (1K01TW011482-01A1; PI A Kay).

Availability of data and materials

The data used for this study is available from the corresponding author upon reasonable request.

Ethics approval

The Eswatini Health and Human Research Review Board (EHHRB) approved this study and a waiver of informed consent for public presentation and publication (EHHRRB B120/2023 ).

Consent for publication

Not Applicable

Competing interests

None declared by the authors.

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No competing interests reported.

Causes of death in people living with HIV in the post 95 -95 -95 era: Lessons from five AIDS Healthcare Foundation clinics in Eswatini

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Abstract

Background

Methods

Results

Discussion

Recommendations/Conclusion

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