Factors Associated with Late Initiation of Highly Active Antiretroviral Therapy among Young HIV-Positive Men and Women Aged 18 to 29 Years in Canada

Abstract

Initiating highly active antiretroviral therapy (HAART) with low CD4 counts or AIDS-defining illnesses (ADIs) increases risk of treatment failure and death. We examined factors associated with late initiation among 18- to 29-year-olds within the Canadian Observational Cohort (CANOC) collaboration, a multi-site study of HIV-positive persons who initiated HAART after 2000. Late initiation was defined as beginning HAART with a CD4 count <200 cells/mm³ and/or having a baseline ADI. Multivariable logistic regression was used to identify independent correlates of late initiation. In total, 1026 individuals (422 from British Columbia, 400 from Ontario, and 204 from Quebec) met our age criteria. At HAART initiation, median age was 27 years (interquartile range, 24, 28 years). A total of 412 individuals (40%) identified as late initiators. Late initiation was associated with female gender, age >25 years at initiation, initiating treatment in earlier years, and having higher baseline viral load. The high number of young adults in our cohort starting HAART late indicates important target populations for specialized services, increased testing, and linkages to care.

Keywords

HIV young adult antiretroviral therapy late initiation Canada

Introduction

It is estimated that in 2011, in Canada, there were approximately 71 300 people living with HIV/AIDS.¹ From 1998 to 2008, young people (age 15-29 years) made up 21% to 23% of HIV-positive diagnoses. The majority of these infections among young people include men who have sex with men (53.9%), heterosexuals (22.9%), and injection drug users (IDUs; 19.4%).² Although highly active antiretroviral therapy (HAART) has improved the health outcomes in people living with HIV, it is important for the medication to be started prior to the person developing an AIDS-defining illness (ADI) or the lowering of the person’s CD4 count.^3,4 Understanding the factors that support or undermine initiation of HAART among young people is essential to design targeted programs that aim to optimize treatment outcomes.

Research has shown that starting antiretroviral medications while asymptomatic significantly delays illness.⁴ People who initiate HAART when their CD4 count is low or they develop ADIs are at greater risk for treatment failure.^3

–9 Also, for people who start treatment late, immune recovery is less likely and they have a greater chance of treatment toxicity and death.¹⁰ Immune reconstitution inflammatory syndrome and other opportunistic infections are also more likely in individuals who initiate treatment late.¹¹

It is also advantageous for people living with HIV to start HAART in a timely manner in order to achieve a suppressed viral load for personal health and for public health reasons.^12

–15 It is now evident that if a person maintains a suppressed viral load, they are significantly less likely to transmit HIV to sexual partners, to IDU partners, and vertically to infants.^14,16
–18 Lower community viral load has been shown to result in a reduction in new infections, which is a major accomplishment for public health.^12,13,15,19

Following the findings of several cohort studies that demonstrated improved health outcomes and survival for individuals who begin HAART at higher CD4 counts,^3,18,20 the International AIDS Society(IAS)-USA 2012 guidelines recommended that all people living with HIV should be offered HAART, regardless of their CD4 count.²¹

Previous research has shown that young people living with HIV are less likely to start medication early due to a myriad of reasons including unstructured lifestyles, lack of family support, and engagement in high-risk activities such as substance use.^22
–24 However, little research has been done to date regarding Canadian young people and their experiences of initiating HAART or has assessed the prevalence and correlates of late initiation among this population across provinces.

Initiation of HAART is an important component of the HIV “Cascade of Care” developed by Gardner et al²⁵ (Figure 1). This spectrum of engagement in care represents an important framework for surveillance and evaluation for HIV treatment. This cascade lays out the road map to achievement of virologic suppression and well-being, with each step representing numerous opportunities to engage with clients and to assist them in successfully moving to the next step. As initiation of HAART is a critical component in the cascade, better understanding of the barriers to timely treatment initiation will help in supporting young people living with HIV to experience the full benefits of HAART. This study therefore seeks to examine the factors associated with late initiation among Canadians aged 18 to 29 initiating HAART in a universal health care setting.

Figure 1.

The Cascade of Care: a spectrum of engagement in HIV care beginning with HIV infection and moving through care to HAART initiation and virologic suppression.²⁵ HAART, highly active antiretroviral therapy.

Methods

Cohort Description

The Canadian Observational Cohort (CANOC) collaboration is a multisite study of antiretroviral-naive HIV-positive persons initiating HAART on or after January 1, 2000. The collaboration is open to all Canadian HIV-treatment cohorts and currently includes 8 participating cohorts from 3 provinces (British Columbia [BC], Ontario [ON], and Quebec [QC]). Eligibility criteria for inclusion were documented HIV infection, residence in Canada, aged 18 years and older, initiation of a first antiretroviral regimen comprising at least 3 individual agents and at least 1 measurement of HIV-1 RNA viral load, and CD4 count within 6 months of initiating HAART.²⁶ Patient selection and data extraction were performed locally at the data centers of the participating cohort studies. Nonnominal data from each cohort were pooled and analyzed in Vancouver, BC. For the current analysis, the last date of follow-up in the cohort was September 30, 2011. All participating cohorts received approval from their institutional ethics boards to contribute nonnominal patient-specific data to the collaboration.

Eligibility Criteria

Our analysis was limited to CANOC participants who initiated HAART between the ages of 18 and 29 years, during the period January 1, 2000, to September 30, 2011.

Primary Outcome

The primary outcome of interest is late initiation defined as beginning HAART when the CD4 count <200 cells/mm³ and/or developing an ADI prior to the start of therapy. The CD4 count of <200 cells/mm³ was selected to account for the evolving guidelines for treatment initiation since study initiation in 2000^27,28 and the fact that this level now represents a very late count at which to initiate HAART.

Covariates of interest included gender, province, hepatitis C coinfection, HIV risk factors, Aboriginal ancestry, baseline CD4 and viral load, composition of initial HAART regimen, year when HAART was started, and follow-up time.

Statistical Analysis

Baseline characteristics were summarized using medians and interquartile ranges (IQRs) for continuous variables and frequencies and proportions for categorical variables. Late versus not late initiators were compared using the Pearson χ² or Fisher exact (categorical variables) and Wilcoxon rank-sum tests (continuous variables).

Univariate logistic regression models were used to identify unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) for variables associated with late initiation. Variables with P < .05 in the univariate analyses were candidates for inclusion in the final possible multivariable logistic regression models for late initiation. Only the correlates with a significant effect (P < .05) remained in the final multivariable model. When multiple covariates measured similar phenomena, the variable representing each construct with the higher effect size and most statistical significance was chosen. All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, North Carolina).

Results

Study Population and Prevalence of Late Initiation

Of the 7738 participants in CANOC, 1026 (13.2%) individuals met the eligibility criteria of initiating HAART between the ages of 18 and 29 years. Of these participants, 334 (32.6%) were women, 686 (66.9%) were men, and 6 (0.6%) were transgender; 422 (41.1%) were from BC, 400 (39.0%) from ON, and 204 (19.9%) from QC (Table 1). In this sample, 412 patients (40.2%) initiated therapy at CD4 counts less than 200 cells/mm³ or had a baseline ADI.

Table 1.

Demographic and Clinical Characteristics of Included Participants at Baseline.^a

Characteristics	Category	n (%)
Gender	Female	334 (32.6)
	Male	686 (66.9)
	Transgender	6 (0.6)
Age, y	<25	383 (37.3)
Age, y	>25	643 (62.7)
Province	British Columbia	422 (41.1)
	Ontario	400 (39.0)
	Quebec	204 (19.9)
Hepatitis C positive	Yes	212 (22.1)
Hepatitis C positive	No	747 (77.9)
History of injection drug use	Yes	218 (29.3)
History of injection drug use	No	525 (70.7)
Men who have sex with men	Yes	347 (46.7)
Men who have sex with men	No	396 (53.3)
Aboriginal ancestry	Yes	76 (16.6)
Aboriginal ancestry	No	381 (83.4)
Initial third ARV class^b	NNRTI	483 (47.1)
	Single PI	155 (15.1)
	Boosted PI	369 (36.0)
	NRTI	19 (1.9)
Initial third ARV agent^b	Nevirapine	133 (13.0)
	Efavirenz	350 (34.1)
	Lopinavir	171 (16.7)
	Atazanavir	208 (20.3)
	Other	164 (16.0)
Viral load, copies/mL	<10 000	226 (22.0)
	10 000-99 999	451 (44.0)
	100 000+	349 (34.0)
ADI	Yes	84 (8.2)
ADI	No	942 (91.8)
CD4 count, cells/mm³	<200	383 (37.3)
	200-349	388 (37.8)
	350+	255 (24.9)
Late initiation	Yes	412 (40.2)
Late initiation	No	614 (59.8)
Late initiation as determined by	CD4 <200 cells/mm³	328 (79.6)
	ADI	29 (7.0)
	CD4 <200 cells/mm³ and ADI	55 (13.3)

Abbreviations: ARV, antiretroviral agent; ADI, AIDS-defining illness; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor.

^a N = 1026.

^b Alongside 2 NRTIs.

Correlates of and Temporal Trends in Late Initiation

In the univariate analysis, late initiation was associated with the province of residence (BC, 48%; ON, 36%; QC, 16%; P < .001), having a positive hepatitis C test (27% versus 19%; P = .003), reporting a history of IDU (37% versus 24%; P < .001), having a baseline viral load of >100 000 copies/mL (51% versus 23%; P < 0.001), being between 25 and 30 years of age at the time of HAART initiation (67% versus 60%, P = .015), starting HAART earlier in terms of calendar year (median year 2005 [IQR: 2002-2007] versus 2007 [IQR: 2004-2009]; P < .001), and longer follow-up time in years (median 4.6 [2.2-7.0] versus 2.8 [1.4-5.4]; P < .001; Table 2).

Table 2.

Comparison of Late versus Nonlate Initiators.^a

Characteristics	Category	Not Late n (%), n = 614	Late n (%), n = 412	P Value
Gender	Female or transgender	194 (31.6)	146 (35.4)	.223
Gender	Male	420 (68.4)	266 (64.5)
Age, y	<25	248 (40.4)	135 (32.8)	.015
Age, y	>25	366 (59.6)	277 (67.2)	.015
Province	British Columbia	225 (36.6)	197 (47.8)	<.001
	Ontario	251 (40.9)	149 (36.2)
	Quebec	138 (22.5)	66 (16)
Hepatitis C positive	Yes	107 (18.7)	105 (27.1)	.003
Hepatitis C positive	No	465 (81.3)	282 (72.9)	.003
History of IDU	Yes	104 (24.1)	114 (36.5)	<.001
History of IDU	No	327 (75.9)	198 (63.5)	<.001
MSM	Yes	222 (51.4)	125 (40.2)	.003
MSM	No	210 (48.6)	186 (59.8)	.003
Aboriginal ancestry	Yes	34 (13.5)	42 (20.5)	.058
Aboriginal ancestry	No	218 (86.5)	163 (79.5)	.058
Initial third ARV class^b	NNRTI	304 (49.5)	179 (43.4)	.046
	Single PI	95 (15.5)	60 (14.6)
	Booster PI	201 (32.7)	168 (40.8)
	NRTI	14 (2.3)	5 (1.2)
		Median (IQR)	Median (IQR)
Year of HAART initiation		2007	2005	<.001
Year of HAART initiation		(2004-2009)	(2002-2007)
Baseline CD4 count, cells/mm³		310 (250-420)	120 (53-170)	<.001
Baseline viral load, log₁₀ copies/mL		4.6 (4.0-5.0)	5.0 (4.5-5.0)	<.001
Total follow-up time, y		2.8 (1.4-5.4)	4.6 (2.2-7.0)	<.001

Abbreviations: IDU, injection drug use; MSM, men who have sex with men; ARV, antiretroviral agent; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; IQR, interquartile range.

^a N = 1026.

^b Alongside 2 NRTIs.

In the multivariable analysis, late initiation was independently associated with being female or transgender (adjusted OR [aOR] = 1.36, 95% CI 1.00-1.84), being older than 25 years of age at the time of HAART initiation (aOR = 1.40, 95% CI 1.05-1.86), starting therapy earlier in terms of calendar year (aOR = 0.88 per year, 95% CI 0.84-0.92), and having a higher baseline viral load (aOR = 5.57, 95% CI 3.71-8.38 for 100 000 + copies/mL versus <10 000; aOR = 1.91, 95% CI 1.30-2.80 for 10 000-100 000 copies/mL versus <10 000; see Table 3).

Table 3.

Factors Associated with Late Initiation of HAART among Young Adults in CANOC.

Variable	Unadjusted Odds Ratio (95% CI)	P Value	Adjusted Odds Ratio (95% CI)	P Value
Gender
Male	1.00	.200	1.00	.050
Female or transgender	1.19 (0.91-1.55)		1.36 (1.00-1.84)
Age > 25, y	1.39 (1.07-1.81)	.013	1.40 (1.05-1.86)	.020
Province
Quebec	1.00		1.00
British Columbia	1.83 (1.29-2.60)	<.001	1.36 (0.93-1.99)	.108
Ontario	1.24 (0.87-1.77)	.235	1.19 (0.82-1.74)	.357
Hepatitis C positive	1.62 (1.19-2.20)	.002
History of IDU	1.81 (1.32-2.49)	<.001
MSM	0.64 (0.47-0.85)	.003
Year of HAART initiation	0.87 (0.83-0.90)	<.001	0.88 (0.84-0.92)	<.001
Baseline viral load, copies/mL
<10 000	1.00		1.00
10 000-100 000	1.73 (1.20-2.50)	.004	1.91 (1.30-2.80)	.001
100 000+	5.18 (3.55-7.57)	<.001	5.57 (3.71-8.38)	<.001

Abbreviations: CI, confidence interval; IDU, injection drug use; MSM, men who have sex with men; HAART, highly active antiretroviral therapy; CANOC, Canadian observational cohort.

The number of individuals starting HAART late has declined since 2000. In 2000, almost half (47.8%) of the individuals started HAART with a baseline CD4 of <200 cells/μL or with an ADI. This proportion decreased to 17.5% in 2010 before increasing slightly to 25% in 2011 (Figure 2).

Figure 2.

Proportion of late initiators by year among young adults in CANOC. CANOC, Canadian observational cohort.

Discussion

Our study demonstrates that nearly half (40.2%) of the HIV-positive young people in CANOC initiated HAART at CD4 counts less than 200 cells/mm³ or with a baseline ADI. Although the proportion starting HAART at CD4 count less than 200 cells/mm³ is decreasing, nearly a quarter continues to initiate HAART late. We also discovered, in multivariable analyses, that female gender, baseline age more than 25 years, starting HAART earlier in terms of calendar year, and higher baseline viral load were independently associated with late initiation. To note, this study was conducted in a setting with universal health care access, without the potential confounding effects of financial barriers to treatment and care.

Consistent with other studies, we found that women were more likely to be late initiators. This may have to do with late presentation and HIV testing due to lack of self-consideration of being at risk and the fear of HIV testing due to stigma. Previous research has shown that women were more likely to die from HIV-related illnesses, without ever accessing treatment.²⁹ Heterosexual men and women who were not involved in injecting drug use were less likely to test, perhaps because their perceived risk is lower than other populations. In Canada, HIV testing is highest among gay men and those who perceive to be at greater risk for HIV.³⁰ A Swiss study showed that gay men were more likely to have had a negative HIV test prior to seroconversion, suggesting that they were more risk aware.⁹ The same study showed late presentation/diagnosis to be the major reason for late initiation of ART.⁹ This finding points to the importance of testing for HIV in women, sometimes a group considered to be at lower risk for HIV, especially in higher income settings.

Individuals between the ages of 25 and 30 years were more likely to start medications later than the younger adults in the study. This finding is in line with past research that has shown older age to be associated with late initiation.^6,31,32 However, previous studies have been conducted with older adult populations where the average age is higher, therefore the population is not necessarily comparable. It is possible that the older individuals in our cohort have psychosocial and structural barriers to care, which are not captured in this analysis. Irrespective of age, linkage to care following an HIV-positive diagnosis depends on the sensitivity of care on the part of the health care team to make the appropriate referrals, in order to receive care and treatment in a timely manner for all those testing positive.

As expected, we found that late initiation was more likely among young people initiating HAART earlier in terms of calendar years. This corresponds with temporal changes in the recommended CD4 count for HAART initiation over time. Treatment guidelines have changed as HAART has evolved, and thus the definition of late initiation of therapy has also changed over our study period.^21,27 However, IAS-USA guidelines from 2000 to 2011 have consistently recommended therapy for all patients with a CD4 count of ≤200 cells/mm³, thus rendering our definition appropriate for the entire study period. Of note, North American guidelines have converged in their recommendation that HAART be offered to all people living with HIV, irrespective of their CD4 count, with the exception of long-term nonprogressors or elite controllers.^21,33

The significant association of late initiation with higher baseline viral load is not surprising, given the well-established biologic association between CD4 count and viral load. In accordance with the natural history of HIV infection, following the clinical latency period, CD4 counts decrease significantly and plasma viremia increases, approaching levels seen during acute infection.³⁴ As HIV plasma viral load is a well-documented key correlate of HIV transmission risk,^12,13,15,19 these findings allude to the importance of earlier HAART initiation for public health in addition to personal health.

Large international cohorts such as the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD),³ Antiretroviral Therapy Cohort Collaboration (ART-CC),³⁵ and the Swiss HIV Cohort Study⁴ have demonstrated that initiation of ART at higher CD4 counts results in better health outcomes compared to those who start therapy at a lower CD4 count. Thus, our findings have important clinical and public health implications. There is a demonstrated need to improve the stage at which young Canadians are initiating HAART.

There were several limitations that readers of this work should consider. First, data were obtained from only 3 provinces, and therefore our results cannot be generalizable to all HIV-positive youth in Canada. Also, there is the potential for missing data. However, to our knowledge, this is the largest sample of HIV-positive young people in Canada analyzed to date. We also acknowledge that young Canadians less than 18 years were not included due to CANOC’s inclusion criteria. Finally, the CANOC database does not contain information on current injection drug use, as this information is not available.

In conclusion, here we have identified a high proportion of late initiation among young HIV-positive men and women accessing care in a universal health care setting. Further efforts are clearly needed to improve earlier HIV testing and subsequent linkage to appropriate care, in order to maximize the benefits of modern treatments at the personal and public health levels. We recommend the incorporation of HIV testing into routine discussions with primary care providers, in an effort to reduce the prevalence of this key component of the HIV Cascade of Care.²⁵

Authors’ Note

The data were presented in part at the XIX International AIDS Conference, July 2012 (Abstract THPE552) and the Canadian Association for HIV Research Conference, April 2013 (Abstract 4208). The CANOC Collaboration includes Investigators: Gloria Aykroyd (Ontario HIV Treatment Network, OHTN), Louise Balfour (University of Ottawa, OHTN Cohort Study [OCS] Coinvestigator), Ahmed Bayoumi (University of Toronto, OCS Coinvestigator), Ann Burchell (OCS Coinvestigator), John Cairney (University of Toronto, OCS Coinvestigator), Liviana Calzavara (University of Toronto, OCS Coinvestigator), Angela Cescon (British Columbia Centre for Excellence in HIV/AIDS), Curtis Cooper (University of Ottawa, OCS Coinvestigator), Kevin Gough (University of Toronto, OCS Coinvestigator), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), P. Richard Harrigan (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Marianne Harris (St. Paul’s Hospital), George Hatzakis (University of Southern California), Robert Hogg (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), Sean Hosein (CATIE), Mark Hull (British Columbia Centre for Excellence in HIV/AIDS), Don Kilby (University of Ottawa, OCS Coinvestigator), Marina Klein (Montreal Chest Institute Immunodeficiency Service Cohort, McGill University), Richard Lalonde (The Montreal Chest Institute Immunodeficiency Service Cohort and McGill University), Viviane Lima (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Mona Loutfy (University of Toronto, Maple Leaf Medical Clinic, OCS Coinvestigator), Nima Machouf (Clinique Medicale l’Actuel, Université de Montréal), Ed Mills (British Columbia Centre for Excellence in HIV/AIDS, University of Ottawa), Peggy Millson (University of Toronto, OCS Coinvestigator), Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), David Moore (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Alexis Palmer (British Columbia Centre for Excellence in HIV/AIDS), Janet Raboud (University of Toronto, University Health Network, OCS Coinvestigator), Anita Rachlis (University of Toronto, OCS Coinvestigator), Stanley Read (University of Toronto, OCS Co-Investigator), Sean Rourke (University of Toronto, OCS Coinvestigator), Marek Smieja (McMaster University, OCS Co-Investigator), Irving Salit (University of Toronto, OCS Coinvestigator), Darien Taylor (Canadian AIDS Treatment Information Exchange, OCS Coinvestigator), Benoit Trottier (Clinique Medicale l’Actuel, Université de Montréal), Chris Tsoukas (McGill University), Sharon Walmsley (University of Toronto, OCS Coinvestigator), and Wendy Wobeser (Queen’s University, OCS Coinvestigator). Analysts and Staff: Guillaume Colley (British Columbia Centre for Excellence in HIV/AIDS), Mark Fisher (OHTN), Sandra Gardner (OHTN), Nada Gataric (British Columbia Centre for Excellence in HIV/AIDS), Sergio Rueda (OHTN), Susan Shurgold (British Columbia Centre for Excellence in HIV/AIDS), and Benita Yip (British Columbia Centre for Excellence in HIV/AIDS).

Footnotes

Acknowledgments

We would like to thank all participants for allowing their information to be a part of the CANOC collaboration, and James Nakagawa for providing digital development expertise. AKP is supported by a CIHR Doctoral Research Award. JMR and CC are supported by Career Scientist Awards from the OHTN. ANB is supported by a CIHR New Investigator Award. MBK is supported by a Chercheur-Boursier Clinicien Senior Career Award from the Fonds de recherche en santé du Québec (FRSQ). JSGM is supported by an Avant-Garde Award from the National Institute on Drug Abuse, National Institutes of Health. MRL receives salary support from CIHR.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CANOC is funded through an Emerging Team Grant from the Canadian Institutes of Health Research (CIHR) and is supported by the CIHR Canadian HIV Trials Network (CTN 242).

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