Reasons for delayed antiretroviral therapy (ART) initiation in the era of early ART initiation guidelines: a retrospective service evaluation

Abstract

Following changes in national antiretroviral therapy (ART) guidelines removing the CD4 threshold for initiation of ART, we evaluated the time to ART initiation and reasons for delayed or non-initiation. A retrospective notes review of 292 newly diagnosed HIV-positive individuals attending two London clinics between August 2015 and December 2016 was performed. Two hundred and fifty-four of 292 (87%) individuals started ART. Median time to ART initiation was 29 days (range: 0–514). Thirty of 292 (13%) did not start ART. Rates of virological suppression at six months were similar regardless of time to ART initiation. People who inject drugs (16.7% vs. 3.6%) (p = 0.009), having a higher median baseline CD4 cell count (500 vs. 388 cells/mm³, p = 0.001), and having gastrointestinal/liver co-morbidities (23% vs. 9%, p = 0.001) were associated with delayed ART initiation. The cohort not on ART had a higher median baseline CD4 cell count (500 vs. 388 cells/mm³, p < 0.001). Documented reasons for delayed or ART non-initiation included patient’s choice, prolonged adjustment periods, and difficulty leaving work. We conclude that delayed or non-initiation of ART was associated with injecting drug use and prolonged adjustment to a new HIV diagnosis. Clinician factors may include lack of urgency with higher baseline CD4 cell counts. Improved linkage to care and drug services pathways may encourage timely ART initiation.

Keywords

Antiretroviral agents HIV infections diagnosis time-to-treatment medication adherence

Introduction

Since publication of the Strategic Timing of Antiretroviral Therapy trial result,¹ antiretroviral (ART) adult treatment guidelines^2,3 have recommended initiation of ART for all people living with HIV (PLWH) irrespective of CD4 cell count, including the British HIV Association (BHIVA) ART guidelines³ in August 2015.

One UK clinic reported excellent acceptance and uptake of ART following implementation of a same-day ART start approach,⁴ which minimises opportunities for patients to disengage with care in the treatment cascade. However, rapid commencement of ART presents challenges. In the absence of data on trends to time to ART initiation following implementation of the 2015 BHIVA guidelines, we evaluated time to start ART in two London HIV centres and reasons for delayed or non-initiation of ART.

Methods

All PLWH attending two London adult HIV services, diagnosed with HIV between 1 August 2015 and 31 December 2016 were included and electronic case notes retrospectively reviewed from baseline until 30 June 2017 or exit from the clinic follow-up. This project was considered to be a service evaluation and did not require research ethical approval by the Trusts’ research committees.

Definitions

Undetectable HIV viral load (VL): ≤200 copies/ml in line with Public Health England.⁵ Delayed ART initiation was defined as >90 days after HIV diagnosis. Poor attenders: individuals who missed >2 appointments in a 12-month period. Loss to follow-up (LTFU): individuals with no clinic attendance for >6 months despite >3 contact attempts. Exclusion criteria: baseline HIV VL ≤200 copies/ml, as unable to assume treatment naive at baseline, and patients who transferred care prior to ART initiation due to lack of ART initiation data. Non-injecting drug use was defined as any reported use of non-prescription substances through any administration route excluding intravenous administration. People who inject drugs (PWID) were defined as people who reported recreational drug use that was administered through the intravenous route.

PLWH were categorized by time from diagnosis to ART initiation: <29 days, 29–90 days, and >90 days. Descriptive and univariate analyses were performed in Minitab™.

Results

Two hundred and ninety-two individuals were included. A summary of the demographics, baseline characteristics, and co-morbidities of the study population, stratified by time to ART initiation, is presented in Table 1.

Table 1.

Univariate analysis of demographics and clinical characteristics of those on ART stratified by time from HIV diagnosis to ART initiation.

	Time from HIV diagnosis to ART initiation			P	PLWH on ART (n = 254)	PLWH not on ART (n = 38)	P
	<29 days (n = 127)	29–90 days (n = 98)	>90 days (n = 29)	P	PLWH on ART (n = 254)	PLWH not on ART (n = 38)	P
Time from HIV diagnosis to ART initiation (days) Median (IQ range)	19 (12–23)	43 (33–57)	149 (120–241)		29 (19–49)	–	–
Gender
Male	105 (83%)	83 (85%)	25 (86%)	0.92	213 (84%)	28 (74%)	0.12
Female	22 (17%)	15 (16%)	4 (14%)		41 (16%)	10 (26%)
Age, years
Median (IQ range)	38 (30–46)	38 (31–50)	36 (28–48)	0.60	37 (31–47)	32 (26–46)	0.58
CD4 cell count,^a cells/mm³
Median (IQ range)	322 (173–496)	407 (246–541)	480 (405–631)	0.001	388 (221–524)	500 (343–732)	0.000
Viral load,^b copies/ml Median (IQ range)	51972 (20663–259067)	40822 (12675–97921)	17581 (7759–29527)	0.081	40822 (15942–122656)	1633 (10258–34560)	0.50
ART regimen^c
NRTI and II	54 (43%)	58 (59%)	18 (62%)	0.003	130 (51%)	–	–
NRTI and PI	53 (41%)	22 (22%)	6 (21%)		81 (32%)	–	–
NRTI and NNRTI	11 (9%)	16 (16%)	6 (21%)		33 (13%)	–	–
NRTI and PI and II	9 (7%)	2 (2%)	0 (0%)		11 (4%)	–	–
Non-injecting drug use^d	42 (33%)	37 (38%)	15 (50%)	0.218	94 (37%)	7 (35%)	0.86
PWID^d	5 (4%)	3 (3%)	5 (17%)	0.009	13 (5%)	4 (11%)	0.008
HBV co-infection^e	2 (2%)	4 (4%)	1 (3%)	0.48	7 (3%)	1 (3%)	0.97
HCV co-infection^f	3 (2%)	6 (6%)	3 (10%)	0.14	11 (4%)	5 (13%)	0.026
Ethnicity
White	68 (55%)	56 (57%)	23 (79%)	0.077	147 (58%)	18 (47%)	0.50
Black	38 (29%)	25 (26%)	5 (14%)		67 (26%)	9 (24%)
Asian	9 (8%)	4 (4%)	0 (0%)		13 (5%)	1 (3%)
Mixed	7 (5%)	8 (8%)	1 (3%)		16 (6%)	5 (13%)
Other	4 (2%)	4 (4%)	1 (3%)		9 (4%)	1 (3%)
Not stated	1 (0%)	1 (0%)	0 (0%)		2 (1%)	4 (11%)
Sexual orientation
MSM	73 (57%)	60 (62%)	21 (72%)	0.271	156 (62%)	22 (65%)	0.77
Heterosexual	53 (40%)	34 (36%)	7 (24%)		95 (38%)	12 (35%)
Not documented	4	2	0		3	4
Comorbidities^g
Endocrine	9 (7%)	6 (6%)	1 (3%)	0.96	17 (7%)	1 (3%)	0.33
Psychiatric	13 (10%)	11 (11%)	7 (24%)	0.13	31 (12%)	8 (21%)	0.14
GI and liver	5 (4%)	15 (15%)	7 (23%)	0.001	27 (1%)	5 (13%)	0.64
AIDS-defining illness	4 (3%)	4 (4%)	1 (3%)	0.89	8 (3%)	0 (0%)	0.27
Malignancy	5 (4%)	4 (4%)	0 (0%)	0.51	9 (4%)	0 (0%)	0.24
Musculoskeletal	4 (3%)	4 (4%)	1 (3%)	0.93	9 (4%)	1 (3%)	0.77
Neurological	4 (3%)	5 (5%)	2 (7%)	0.62	11 (4%)	0 (0%)	0.19
Cardiovascular	3 (2%)	1 (1%)	2 (7%)	0.21	5 (2%)	2 (5%)	0.23
Infectious	3 (2%)	8 (8%)	2 (7%)	0.13	12 (5%)	1 (3%)	0.56
Renal	3 (2%)	4 (4%)	1 (3%)	0.73	5 (2%)	0 (0%)	1.00
Respiratory	6 (5%)	5 (5%)	1 (3%)	0.92	12 (5%)	0 (0%)	0.17
Hypertension	8 (6%)	11 (11%)	1 (3%)	0.24	19 (7%)	4 (11%)	0.52
Skin	3 (2%)	8 (8%)	2 (3%)	0.13	13 (5%)	2 (5%)	0.97
Metabolic	6 (5%)	3 (3%)	1 (1%)	0.80	10 (4%)	1 (3%)	0.69

ART: antiretroviral therapy; GI: gastrointestinal; HBV: hepatitis B virus; HCV: hepatitis C virus; MSM: men who have sex with men; NRTI: nucleoside reverse transcriptase inhibitors; NNRTI: non-nucleoside reverse transcriptase inhibitors; PI: protease inhibitors; PWID: people who injected drug; PLWH: people living with HIV; II: integrase inhibitors; VL: viral load.

Boldface numbers represent significant results.

Twelve individuals did not have initial CD4 cell counts due to being lost to follow-up (LTFU).

Fourteen individuals did not have initial VL measurements (LTFU).

Thirty-eight individuals did not start ART.

Eighteen individuals with unknown recreational drug use histories.

Eight individuals with unknown hepatitis B status.

Seven individuals with unknown hepatitis C status.

Eleven individuals with unknown comorbidities.

Of the 292 individuals, 254 (87%) started ART during the study period. Median time to ART initiation was 29 days (range: 0–514); 225/254 (89%) within 90 days. Thirty of 292 (13%) did not start ART. The median time between diagnosis and ART initiation did not change during the study. Also, 201/205 (98%) had HIV VL ≤200 copies/ml by six months following ART initiation, and 49 individuals transferred care or were lost to follow-up following ART initiation. Rates of virological suppression at six months were similar regardless of time to ART initiation (>90 days: 95% vs. 29–90 days: 97% vs. <29 days: 99%, p = 0.648).

PWID (p = 0.009), higher median CD4 cell count (500 vs. 388 cells/mm³, p = 0.001) and gastrointestinal/liver problems (p = 0.001) were associated with delayed ART initiation.

The cohort not on ART had a higher median baseline CD4 cell count (500 vs. 388 cells/mm³, p < 0.001) than those on ART. PWID (11% vs. 5%, p = 0.008) and chronic hepatitis C infection (13% vs. 4%, p = 0.026) were associated with not being on ART. Gender, age, sexual orientation and co-morbidities did not differ significantly regardless of ART status (Table 1).

Reasons for delayed or non-initiation of ART are summarised in Table 2. Four of 29 (14%) individuals with delayed ART initiation and 7/30 (23%) who did not initiate ART had no information available.

Table 2.

Reasons for delayed start or not starting ART.^a

	Delayed ART start>90 days from diagnosis (n = 29)	Not started ART during study period (n = 30)
Individual choice	8 (28%)	2 (6%)
Left UK	5 (17%)	5 (17%)
Poor attender	3 (10%)	5 (17%)
Delayed initial appointment due to work	3 (10%)	0 (0%)
Prolonged adjustment period to HIV diagnosis	3 (10%)	0 (0%)
Language barrier	2 (7%)	0 (0%)
Mental health issues	2 (7%)	3 (10%)
Clinical reasons	2 (7%)	0 (0%)
Injecting drug use	1 (3%)	2 (7%)
Lost to follow-up	0 (0%)	6 (20%)
Deceased	0 (0%)	1 (3%)
Reason not documented	4 (14%)	7 (23%)

Seven individuals transferred their care prior to starting ART and were excluded from the analysis.

More than one reason per patient may be documented.

Limitations

With a retrospective review of case notes, there were a significant proportion of undocumented fields, resulting in limited quality of data recorded. Patients who were LTFU or transferred care to different centres following their diagnosis but prior to ART initiation may have initiated ART elsewhere.

Discussion

The association between delayed ART initiation and high CD4 cell counts may reflect a lag in clinician uptake of the current recommendations, with a lack of clinical urgency to start ART. PWID, patient’s choice, prolonged adjustment periods, and difficulty taking time off work were reasons linked to delayed ART initiation. This reflects the psycho-social complexities faced by patients on initiating ART and agrees with reports that concerns about treatment adherence,^6,7 engagement in health-care facilities,⁸ drug–drug interactions,⁹ and limited integration between HIV and mental health services have been linked to delays in ART initiation in the literature. LTFU rates were high compared to other UK cohorts where LTFU has been reported at around 5% in any one year.¹⁰ ART adherence was not affected by the time to ART initiation, allaying concerns for the impact of rapid ART initiation on ART adherence. Delayed ART initiation was associated with less likelihood of protease inhibitor-based ART regimens, which may reflect the availability of genotype results; however, other reasons such as concerns over drug interactions or ART side effects profile may also contribute to the hesitancy of ART initiation.

In conclusion, there remains a significant minority of PLWH who experience delayed or non-ART initiation. Clinician factors may include a lack of urgency to start ART with higher baseline CD4 cell counts. Patient factors include intravenous drug use, prolonged adjustment periods, or concerns over ART initiation. Further qualitative work will contribute to exploring both clinician and patient factors for delayed or non-initiation of ART after HIV diagnosis. As a result of this service evaluation, strategies to shorten the time from diagnosis to first appointment to discuss starting ART with patients, and improved mental health, substance misuse, and alcohol screening at each clinic visit are being implemented. Improving diagnosis and onward referrals for PLWH who require access to mental health and drug rehabilitation services will support the initiation of ART in a timely manner.

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJL reports personal fees from Gilead Sciences Inc., outside the submitted work. WM reports personal fees from Gilead Sciences Inc., ViiV Healthcare, and Bristol-Myers Squibb, outside the submitted work. All other authors have nothing to declare.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: SF is funded through Imperial College NIHR BRC.

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