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.
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 al 25 (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.
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
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.
Demographic and Clinical Characteristics of Included Participants at Baseline.a
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%;
Comparison of Late versus Nonlate Initiators.a
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).
Factors Associated with Late Initiation of HAART among Young Adults in CANOC.
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).
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 Study 4 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
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
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).