DOI: 10.1111/hiv.12212 HIV Medicine (2015), 16, 337–345
© 2015 British HIV Association
ORIGINAL RESEARCH
Declines in highly active antiretroviral therapy initiation at CD4 cell counts ≤ 200 cells/μL and the contribution of diagnosis of HIV at CD4 cell counts ≤ 200 cells/μL in British Columbia, Canada L Lourenço,1 H Samji,1 A Nohpal,1 W Chau,1 G Colley,1 K Lepik,1 R Barrios,1 V Lima,1,2 RS Hogg,1,3 JSG Montaner,1,2 S Kesselring1 and DM Moore1,2 1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada, 2Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada and 3Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada Objectives
The aim of the study was to examine trends in initiating highly active antiretroviral therapy (HAART) with a CD4 count ≤ 200 cells/μL and the contribution of having a CD4 count ≤ 200 cells/μL at the time of diagnosis to these trends, in British Columbia (BC), Canada. Methods
We included in the analysis treatment-naïve BC residents aged ≥ 19 years who initiated HAART from 2003 to 2012. Participants were classified as follows: Group 1: diagnosed and initiated HAART with a CD4 count > 200 cells/μL; Group 2: diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL; and Group 3: diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL. We measured trends in initiating HAART with a CD4 count ≤ 200 cells/μL and used logistic regression models to measure factors associated with initiating HAART with a CD4 count ≤ 200 cells/μL, stratified by having a CD4 count ≤ 200 cells/μL or > 200 cells/μL at the time of diagnosis. Results
Between 2003 and 2012, 3506 BC residents initiated HAART. Of these, 44% (1558 of 3506) initiated HAART with a CD4 count ≤ 200 cells/μL. This proportion declined from 69% (198 of 287) in 2003 to 21% (81 of 330) in 2012 (P < 0.001). The proportion of those in Group 3 increased from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2012 (P < 0.001). Overall, 56% (1948), 22% (776) and 22% (782) made up Groups 1, 2, and 3, respectively. In adjusted analyses, seeing a specialist was significantly associated with being in Group 3. Using injection drugs and seeing a specialist were associated with being in Group 2. Conclusions
In recent years, among individuals who ever initiated HAART in BC, being diagnosed with low CD4 cell counts has become a greater contributor to initiating HAART with low CD4 cell counts. Keywords: diagnosis, highly active antiretroviral therapy, HIV, late initiation, late presentation. Accepted 9 October 2014 to a chronic, manageable condition. HAART acts to reduce viral load in the blood with the benefit of delaying the progression of HIV/AIDS and mortality associated with it [1–5], allowing individuals to live near-normal lifespans [6]. In addition, HAART has been shown to be highly effective in the prevention of HIV transmission [7,8]. However, the benefits of HAART, at both the individual and the societal level, are reduced among
Introduction Highly active antiretroviral therapy (HAART) has dramatically transformed HIV infection from a fatal disease Correspondence: Lillian Lourenço, Epidemiology and Population Health Program, British Columbia Centre for Excellence in HIV/AIDS, 680–1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel: (604) 682 2344 Ext. 66275; fax: (604) 806 9044; e-mail: [email protected]
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individuals who initiate treatment late in the course of their illness [1]. Late HAART initiation, typically defined as starting treatment with a CD4 cell count of ≤ 200 cells/μL, has been shown to limit the therapeutic benefit of HAART and is associated with an increased risk of both AIDS- and nonAIDS-related clinical events and mortality [3,9–16]. The UK Collaborative HIV Cohort Study estimates that life expectancy decreases by over 10 years in individuals initiating antiretroviral therapy with CD4 cell counts < 200 cells/μL compared with individuals starting at 200 to 350 cells/μL [10]. Furthermore, late HAART initiation has been found to be associated with impaired CD4 recovery [1,17,18] and a reduced likelihood of achieving virological suppression [15,16]. HIV treatment recommendations on when to initiate HAART have changed over time. In 1996, when HAART first became available, physicians offered HAART regardless of CD4 cell count. In 2000, with growing concerns about HAART-related toxicities and side effects, as well as the emerging threat of HIV drug resistance, the International Antiviral Society-USA (IAS-USA) HIV treatment guidelines recommended delaying HAART initiation among asymptomatic patients, until CD4 cell counts declined to ≤ 200 copies/μL [19]. Over time, starting in 2002, with increasing awareness and understanding of the harmful effects of late HAART initiation and treatment interruptions coupled with the increasing availability of safer, simpler and better tolerated regiments, the IAS-USA guidelines moved to recommend HAART initiation at higher CD4 cell counts, to < 350 cells/μL in 2008, and to ≤ 500 cells/μL in 2010 [20–23]. More recently, IAS-USA guidelines recommend that HAART be offered to all HIVinfected persons regardless of CD4 cell count, except for elite controllers [24,25]. Treatment guidelines in BC have remained consistent with those of the IAS-USA since 1996. We examined trends in initiating HAART with a CD4 cell count of ≤ 200 cells/μL among BC residents from 2003 to 2012 and investigated characteristics of these individuals. Furthermore, we examined trends in the contribution of being diagnosed with a CD4 cell count ≤ 200 cells/μL to initiating HAART with a CD4 cell count ≤ 200 cells/μL in this population.
Methods We conducted a retrospective cohort analysis of all individuals enrolled in the HAART Observational Medical Evaluation and Research (HOMER) cohort who initiated HAART between 1 January 2003 and 31 December 2012 [26]. The HOMER cohort is made up of individuals in the British Columbia HIV/AIDS Drug Treatment Program (DTP) who: (i)
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were ≥ 19 years of age at the time of HAART initiation, (ii) started the program antiretroviral therapy-naïve, (iii) were on two nucleosides/nucleotides alongside either a protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted PI, (iv) had a baseline CD4 count and plasma viral load (pVL) measurement conducted within 6 months prior to antiretroviral initiation, and (v) for those who initiated HAART between 1 January 2003 and 31 December 2010, had a baseline pVL > 5000 copies/mL; for those who initiated HAART between 1 January 2011 and 31 December 2012, had a baseline pVL > 50 copies/mL. Further details of the HOMER cohort have been previously described [27,28]. The BC Centre for Excellence in HIV/AIDS (BC-CfE) has been responsible for the distribution of HAART at no cost for all eligible BC residents since 1992 [27]. The BC-CfE’s DTP has received ethical approval from the University of British Columbia Ethics Review Committee at the St Paul Hospital site. In order for individuals to enroll in the DTP, their physicians must complete a drug request form which acts as a legal prescription. These forms collect patient demographic information as well as CD4 cell counts, hepatitis serology, some HIV-risk behaviour data, and HAART treatment history. Prescriptions are renewed every one to three months. All pVL testing conducted in BC is performed at the St Paul’s Hospital Virology Laboratory using the Roche Amplicor Monitor assay (Roche Diagnostics, Laval, Quebec, Canada) by either the standard method or the ultrasensitive adaptation. CD4 cell counts are measured by flow cytometry, followed by fluorescent monoclonal antibody analysis (Beckman Coulter, Inc., Mississauga, Ontario, Canada). Approximately 85% of all CD4 testing performed in BC is performed at St Paul’s Hospital in Vancouver. These laboratory data are captured by regular linkages with the laboratory database and that of the DTP registry. CD4 cell counts that are not captured through the laboratory data linkage are obtained through the prescription forms.
Study design and statistical analyses We categorized our study population into three groups: (i) those who were diagnosed with a first-ever CD4 cell count > 200 cells/μL and had a CD4 cell count > 200 cells/μL at the time of HAART initiation (diagnosed and initiated HAART with a CD4 count > 200 cells/μL); (ii) those who were diagnosed with a first-ever CD4 cell count > 200 cells/μL and had a CD4 cell count ≤ 200 cells/μL at the time of HAART initiation (diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL), and (iii) those who were diagnosed with a first-ever CD4 cell count ≤ 200 cells/μL and had a CD4 cell
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count ≤ 200 cells/μL at the time of HAART initiation (diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL). As we did not have HIV diagnosis date data, we made several assumptions when assembling these three groups in instances when it was not clear whether the available CD4 cell count was an individual’s first-ever CD4 cell count: (i) HOMER participants with an available baseline CD4 cell count but lacking a first-ever CD4 cell count were excluded from the analysis if a VL measurement was performed prior to their baseline VL measurement (n = 135), because it could not be safely assumed that the baseline CD4 count was their first-ever CD4 cell count. Of these individuals, 79% were male, and they had a median age of 44 years (25th−75th percentile 36–51 years) and a median baseline CD4 cell count of 120 (25th–75th percentile 40–170) cells/ μL; (ii) If a participant only had a baseline CD4 count available and no other previous CD4 counts or VL results, then it was assumed that this was the individual’s first CD4 count and, if that CD4 count was ≤ 200 cells/μL, the individual was considered to be in the ‘diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’ group (n = 200). (iii) DTP participants who had a baseline CD4 count ≥ 200 cells/μL and no evidence of prior pVL or CD4 count measurement were assumed to have been diagnosed early (n = 145). (iv) Those who had a baseline CD4 count ≥ 200 cells/μL with no available first CD4 count but an available first pVL (which corresponded in time with the baseline CD4 count) were classified as ‘diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ (n = 158). We examined trends in the proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL and the contribution of being diagnosed with a CD4 count ≤ 200 cells/μL over a 10-year period (2003–2012), using the Cochran−Armitage test of trend. We also conducted a sensitivity analysis using a CD4 count threshold of ≤ 350 cells/μL at the time of diagnosis and HAART initiation. We conducted bivariable analyses of sociodemographic, clinical, and laboratory variables, comparing those in the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL with: (i) those in the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those in the group who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL. In addition, we compared two physician-related variables (i): service provider group (specialist vs. nonspecialist), which describes whether the physician who prescribed the first-ever HAART prescription was a specialist or not, and (ii) ‘physician experience’, which was defined as the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual over the
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preceding 2 years. Categorical variables were compared using the Fisher exact test and continuous variables were compared using the Wilcoxon rank-sum test. Finally, two logistic regression models were developed. We modelled how (i) those in the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those in the group who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL, differed from those in the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL. Univariate logistic regression models were used to identify variables associated with these models. Variables with P < 0.05 in the univariate analyses were candidates for inclusion in the final possible multivariate logistic regression model. A backward stepwise technique was used in the selection of covariates to build these models [29]. To minimize the potential for collinearity, we assessed correlation between pairs of independent variables. The selection of variables was based on two criteria: the Akaike information criterion (AIC) and Type III P-values. All analyses were performed using SAS software version 9.3 (SAS Institute, Cary, NC).
Results Between 1 January 2003 and 31 December 2012, a total of 3506 antiretroviral therapy-naïve HIV-positive individuals 19 years of age or older initiated HAART and were eligible for study analysis. Of these, 81.5% were male and the median age was 42 years (25th–75th percentile 35 to 49 years) at the time of HAART initiation. A total of 20% (696) had a reported history of injecting drug use (IDU), 17% (596) were men who had sex with men (MSM), 7% (260) of study participants were identified as having heterosexual exposure to HIV, and 56% (1954) had either no risk category information, were infected by either blood transfusion or perinatal exposure, or were categorized as having an unknown risk (i.e. risk factor not identified). Overall, 44% (1558) of eligible study individuals initiated HAART with CD4 cell counts ≤ 200 cells/μL. The proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL declined over the study period from a high of 69% (198 of 287) starting late in 2003 to a low of 21% (81 of 386) in 2012 (Fig. 1; P < 0.001 for test of trend). When categorized on the basis of CD4 cell counts at diagnosis and HAART initiation, 56% (1948 of 3506) were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, 22% (776 of 3506) were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL, and 22% (782 of 3506) were diagnosed and initiated HAART with a CD4 count > 200 cells/μL (Table 1). An additional 14 individuals
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Fig. 1 Number of highly active antiretroviral therapy (HAART)-naïve individuals initiating HAART with a CD4 cell count ≤ 200 cells/μL and diagnosed with a CD4 cell count ≤ 200 cells/ μL from 2003 to 2012 in British Columbia, Canada. *The proportion of indiviudals initiating HAART with a CD4 cell count ≤ 200 cells/μL among those who initiated HAART. **The proportion of individuals diagnosed with a CD4 cell count ≤ 200 cells/μL among those who initiated HAART late with a CD4 cell count ≤ 200 cells/μL.
(0.3%) had at least one CD4 cell count ≤ 200 cells/μL prior to HAART initiation, but their most recent CD4 cell count prior to starting HAART was > 200 cells/μL. These individuals were excluded from further analyses. Among those who initiated treatment with a CD4 count ≤ 200 cells/ μL, the proportion with a CD4 count ≤ 200 cells/μL at diagnosis increased over the study period from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2013 (P < 0.001 for test of trend). Our sensitivity analysis found that 52% (150 of 287) of participants initiated HAART with a CD4 count ≤ 350 cells/μL in 2003 and 28% (110 of 380) initiated HAART with a CD4 count ≤ 350 cells/μL in 2012 (P < 0.001 for test of trend). Similarly, among those who initiated treatment with a CD4 count ≤ 350 cells/μL, the proportion of those diagnosed with a first CD4 count ≤ 350 cells/μL increased over time from 56% in 2003 to 65% in 2013 (P < 0.001 for test of trend). The median CD4 count at the time of HAART initiation from 2008 to 2012 was 200 cells/μL (25th−75th percentile 80–290 cells/μL). Baseline characteristics of our study population, comparing those who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL with (i) those who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL, are summarized in Table 1.
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In our multivariate logistic regression models, we included an IDU risk variable (yes/no/unknown) instead of the risk category variable because the risk category variable had over 50% unknown data and the IDU risk variable had the least amount of missing data. In the multivariate logistic regression model comparing the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL with the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, we found that having a history of IDU [adjusted odds ratio (aOR) 2.73; 95% confidence interval (CI) 2.23–3.35] and seeing a physician with less HAART prescribing experience (aOR 1.06; 95% CI 1.03–1.09) were independently associated with being diagnosed with a CD4 count > 200 cells/μL and initiating HAART with a CD4 count ≤ 200 cells/μL (Table 2, model 1). Seeing a specialist was found to be approaching statistical significance (aOR 1.20; 95% CI 1.00–1.44). However, having an unknown Aboriginal ethnicity was associated with having a reduced odds of initiating HAART with a CD4 cell count ≤ 200 cells/μL (aOR 0.71; 95% CI 0.58−0.88). Comparing those who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL with those who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, we found that having a specialist prescribe an individual’s first HAART regimen (aOR 2.77; 95% CI 2.30–3.33) was independently associated with being
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Table 1 Bivariate analyses comparing individuals who were diagnosed and initiated highly active antiretroviral therapy (HAART) with a CD4 cell count > 200 cells/μL with individuals who were: (i) diagnosed with a CD4 cell count > 200 cells/ μL and initiated HAART with a CD4 cell count ≤ 200 cells/ μL and (ii) diagnosed and initiated HAART with a CD4 count cell count ≤ 200 cells/ μL
Variable Gender [n (%)] Female Male Ethnicity [n (%)] Aboriginal Non-Aboriginal Unknown Hepatitis C [n (%)] Positive Negative Unknown AIDS diagnosis [n (%)] Yes No HIV risk factors [n (%)] Heterosexual IDU MSM Other/unknown Service provider group* [n (%)] Specialist Nonspecialist Age at HAART initiation (years) Median (25th-75th percentile) Baseline viral load (log10 copies/ml) Median (25th-75th percentile) Time between first plasma viral load and HAART initiation (years)† Median (25th-75th percentile) Physician experience‡ Median (25th-75th percentile)
Total n (%)
Diagnosed and initiated HAART with a CD4 count > 200 cells/μL n = 1948
Diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL n = 776
649 (19) 2857 (81)
342 (18) 1606 (82)
155 (20) 621 (80)
0.153
152 (19) 630 (81)
0.249
414 (12) 1115 (32) 1977 (56)
197 (10) 553 (28) 1198 (62)
114 (15) 289 (37) 373 (48)
< 0.001
103 (13) 273 (35) 406 (52)
< 0.001
1246 (36) 2029 (58) 231 (7)
575 (30) 1235 (63) 138 (7)
391 (50) 342 (44) 43 (6)
< 0.001
280 (36) 452 (58) 50 (6)
0.006
478 (14) 3028 (86)
103 (5) 1845 (95)
120 (15) 656 (85)
< 0.001
255 (33) 527 (67)
< 0.001
260 (7) 1217 (35) 646 (18) 1383 (39)
125 (6) 333 (17) 360 (18) 1130 (58)
44 (6) 196 (25) 117 (15) 419 (54)
< 0.001
91 (12) 167 (21) 119 (15) 405 (52)
< 0.001
1788 (51) 1718 (49)
837 (43) 1111 (57)
411 (15) 365 (47)
< 0.001
540 (69) 242 (31)
< 0.001
42 (35–49) 4.91 (4.44–5.00)
41 (34–49) 4.71 (4.26–5.00)
42 (35–48) 5.00 (4.69–5.00)
1 (0–4)
2 (0–4)
3 (1–6)
126 (47–277)
139 (58–283)
116 (41–286)
P1
0.373 < 0.001
< 0.001 0.018
Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL n = 782
43 (37–50) 5.00 (4.85–5.18)
P2
< 0.001 < 0.001
1 (0–2)†
< 0.001
87 (38–244)
< 0.001
*The type of service provider who provided the first-ever HAART prescription. †Time between first plasma viral load and treatment initiation for individuals in the ‘Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’ group is reported in months. ‡Physician experience refers to the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual, over the preceding 2 years (per 100 patients). P1 represents the p-value between the groups ‘Diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ and ‘diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL’. P2 represents the p-value between the groups ‘Diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ and ‘diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’. Hepatitis C, history of having an antibody positive Hepatitis C test; IDU, history of injection drug use; MSM, Men who have sex with men.
diagnosed and initiating HAART with a CD4 count ≤ 200 cells/μL (Table 2, model 2). Having an unknown Aboriginal ethnicity was associated with having a reduced odds of initiating HAART with a CD4 count ≤ 200 cells/μL (aOR 0.78; 95% CI 0.64–0.97). Having a physician with less HAART prescribing experience was approaching statistical significance for having increased odds of being diagnosed and initiating HAART with a CD4 count ≤ 200 cells/μL (aOR 0.97; 95% CI 0.95–1.00).
Discussion Our results demonstrate that the number and proportion of antiretroviral therapy-naïve individuals initiating
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HAART with a CD4 count ≤ 200 cells/μL declined significantly from 69% in 2003 to 21% in 2013. In addition, the absolute number of individuals initiating HAART with a CD4 count ≤ 200 cells/μL also declined from 198 in 2003 to 81 in 2013. These results are comparable to results from other HAART distribution programmes in industrialized countries, which have ranged from 23% to 65% [12,16,30,31]. In addition, we showed that, among individuals who initiated HAART, the contribution of being diagnosed with a CD4 count ≤ 200 cells/μL to the proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL increased over the study period from approximately 49% in 2003 to over 69% in 2012.
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Table 2 Multivariable logistic regression model comparing those who initiated highly active antiretroviral therapy (HAART) with a CD4 cell count ≤ 200 cells/ μL with those who initiated with higher CD4 cell counts stratified on the basis of CD4 cell count at HIV diagnosis
Variable Gender Male Female Ethnicity Non-Aboriginal Aboriginal Unknown Injecting drug user history No Yes Unknown Service provider group* Nonspecialist Specialist Age at HAART initiation (per decade) Physician experience†
Model 1
Model 2
Diagnosed and initiated HAART with a CD4 count > 200 cells/μl versus Diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL
Diagnosed and initiated HAART with a CD4 count > 200 cells/μL versus Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
P
1.00 1.17 (0.95–1.45)
0.141
1.00 1.11 (0.85–1.45) 0.60 (0.50–0.72)
< 0.001
1.00 0.85 (0.63–1.13) 0.71 (0.58–0.88)
1.00 2.59 (2.14–3.13) 0.95 (0.75–1.20)
< 0.001
1.00 1.50 (1.27–1.77) 1.03 (0.95–1.12)
< 0.001
1.05 (1.03–1.08)
Unadjusted OR (95% CI)
P
NS
Adjusted OR (95% CI)
P
P
1.00 1.13 (0.92–1.40)
0.249
NS
0.006
1.00 1.06 (0.80–1.40) 0.69 (0.57–0.83)
< 0.001
1.00 0.97 (0.71–1.31) 0.78 (0.64–0.97)
0.052
1.00 2.73 (2.23–3.35) 1.18 (0.91–1.53)
< 0.001
1.00 1.20 (1.00–1.44) 0.46 (0.36–0.58)
< 0.001
1.00 1.15 (0.94–1.41) 0.58 (0.44–0.76)
< 0.001
0.053
1.00 2.96 (2.48–3.53) 1.21 (1.12–1.31)
< 0.001 < 0.001
1.00 2.77 (2.30–3.33) 1.21 (1.11–1.31)
< 0.001
0.425
1.00 1.20 (1.00–1.44) NS
< 0.001
1.06 (1.03–1.09)
< 0.001
1.01 (0.98–1.04)
0.41
0.97 (0.95–1.00)
0.060
< 0.001
OR, odds ratio; CI, confidence interval; *Service Provider Group: The type of service provider who provided the first-ever HAART prescription. †Physician experience refers to the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual, over the preceding 2 years (per 100 patients). NS, not selected.
Our results imply that modifications to HAART guidelines and other efforts to promote earlier initiation of HAART have been effective. However, it also highlights the need to improve timely diagnosis of HIV infection in BC. This is especially true in the context of treatment as prevention programmes which rely on timely HIV diagnosis and HAART initiation to ensure programme success. Our finding that diagnosis with a CD4 count ≤ 200 cells/μL has become a greater contributor to initiating HAART at very low CD4 cell counts suggests that increased routine testing is necessary to uncover the undiagnosed population during the early stage of their HIV disease. HIV testing guidelines which recommend increased universal testing in primary care, such as those from the US Centers for Disease Control and Prevention [32], may aid in earlier diagnosis of these individuals. In 2011, a pilot programme which introduced routine HIV testing in hospitals and in primary care clinics was implemented in the city of Vancouver, BC [33]. The programme has observed a dramatic increase in HIV testing rates, with high acceptance by patients. This intervention resulted in an additional 40 HIV diagnoses, in patients who were not likely to have been otherwise offered a test for diagnosis (as indicated by the number of medical care visits prior to diagnosis). The results of this present study and the
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above-mentioned pilot study support the recent implementation of new HIV testing guidelines in BC which recommend additional routine testing in health care settings, even for patients without identifiable risk factors for HIV infection [34]. Our finding that individuals who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL were more likely to have received a first HAART prescription from a specialist vs. a nonspecialist probably does not mean that specialists are more likely to delay treatment initiation. Rather, it suggests that specialists are more likely to see patients who have advanced HIV disease. Indeed, in our study sample, 69% of individuals diagnosed late were treated by a specialist. This does suggest that the pool of referrals from which physicians refer to a specialist is more likely to have individuals who are either not engaged in care or diagnosed with HIV infection late in the course of their illness. This observation warrants further investigation. We found a weak association between physicians with less HAART prescribing experience and initiating HAART with a CD4 count ≤ 200 cells/μL. This finding suggests that physicians with less HIV care experience may benefit from enhanced support from more experienced HIV-treating physicians. We did perform a subanalysis to explore
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whether or not a threshold could be determined which would indicate the target physician population who would benefit from such an intervention (data not shown). However, we did not find that such a threshold existed. Still, efforts should be made to improve support for those physicians with less HAART prescribing experience. We found that persons with a history of IDU were more likely to be diagnosed with a CD4 cell count > 200 cells/μL and to initiate HAART with a CD4 count ≤ 200 cells/μL. This result probably reflects the difficulty in engaging persons with a history of IDU in effective care [35]. It may also reflect physician unwillingness to initiate people who use injection drugs on HAART because of concerns regarding HAART adherence and possible subsequent development of HAART resistance mutations [35–38]. Continuing professional development regarding HAART use and engaging marginalized populations in care may help in this regard. It is worth noting that several studies have demonstrated that physicians have poor predictive ability with respect to levels of adherence among people who inject drugs [37,39] and most injection drug users will achieve satisfactory outcomes when on HAART [35]. Our study had several limitations. First, the DTP database does not systematically collect HIV diagnosis dates. Therefore, we used the first-ever recorded CD4 cell count date as a proxy for HIV diagnosis date. This is a reasonable assumption in our setting, as most patients who receive an HIV diagnosis would be offered a viral load and CD4 cell count measurement at the next follow-up visit, at no cost. Secondly, our analysis was limited to only those individuals who ever initiated HAART and did not include those who never initiated HAART. This limits the generalizability of our results. However, given the universal accessibility of health care and HIV treatment in BC, we feel that the number of individuals who are diagnosed with HIV infection and who do not eventually receive ART is probably quite small. Indeed, an analysis using BC vital statistics data which included all HIV-positive individuals, regardless of whether or not they had ever accessed ART, found that the number of HIV-related deaths in BC decreased from 127 individuals in 2003 to 59 in 2011 (this corresponds to a decrease in the mortality rate from 3.1 to 1.3 from 2003 to 2011), suggesting that very few individuals are dying from HIV infection in BC without ever accessing ART [40]. Thirdly, there were a large number of unknowns in the HIV risk and ethnicity categories. This limited our ability to carry out further risk-based stratifications. In conclusion, our analysis provides valuable insight into trends in initiating HAART with a CD4 cell count ≤ 200 cells/μL in BC and the contribution of being diagnosed at very low CD4 cell counts to these trends. Our results demonstrate that initiating HAART at very low CD4
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cell counts is becoming less common but also highlights that having CD4 cell counts ≤ 200 cells/μL at the time of diagnosis is rapidly becoming the main determinant of initiating HAART at very low CD4 cell counts. This highlights the need to improve strategies to diagnose HIVinfected individuals much earlier in the course of their HIV infection. In this regard, the recent adoption of routine HIV testing guidelines in BC represents a very favourable development.
Acknowledgements We thank the participants in the BC HIV/AIDS Drug Treatment Program and the physicians, nurses, social workers and volunteers who support them. Conflicts of interest: This study received limited unrestricted funding from Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. The funding provided by the commercial sources has been directed to the institution and not to the investigators. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the HIV Medicine policies on sharing data and materials. Sources of support: DMM is supported by a Scholar Award from the Michael Smith Foundation for Health Research. JSGM is supported by the British Columbia Ministry of Health and by the US National Institutes of Health (1DP1DA026182 and R01DA036307). He has also received limited unrestricted funding from Abbvie, BristolMyers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. VDL is supported by a Scholar Award from the Michael Smith Foundation for Health Research, a New Investigator Award from CIHR and two grants from the Canadian Institutes of Health Research (MOP-125948) and the US National Institute on Drug Abuse (R03DA03385101). The funders had no role in the design, data collection, data analysis, data interpretation, or writing of the report. The remaining authors report no disclosures. Author contributions: LL, HS, DM, KL, BH, VDL, JSGM and GC contributed to the conception and design of the study. AN, GC and WC performed all statistical analyses. LL and DM drafted the manuscript. DM and JSGM advised on all aspects of the study. All authors revised the manuscript critically and approved the final version submitted for publication.
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in a multicenter study in Italy. J Acquir Immune Defic Syndr 2004; 36: 951–959. 13 Ellis RJ, Badiee J, Vaida F et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011; 25: 1747–1751. 14 Sterne JAC, May M, Costagliola D et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009; 373: 1352–1363. 15 Perez-Molina JA, Diaz-Menendez M, Plana MN, Zamora J, Lopez-Velez R, Moreno S. Very late initiation of HAART impairs treatment response at 48 and 96 weeks: results from a meta-analysis of randomized clinical trials. J Antimicrob Chemother 2012; 67: 312–321. 16 Perez-Molina JA, Suarez-Lozano I, Del Arco A et al. Late initiation of HAART among HIV-infected patients in Spain is frequent and related to a higher rate of virological failure but not to immigrant status. HIV Clin Trials [Multicenter Study Research Support, Non-U.S. Gov’t]. 2011; 12: 1–8. 17 Kelley CF, Kitchen CM, Hunt PW et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2009; 48: 787–794. 18 Garcia F, de Lazzari E, Plana M et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to
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Panel. JAMA [Consensus Development Conference Guideline Practice Guideline Research Support, Non-U.S. Gov’t Review]. 2002; 288: 222–235. 20 British Columbia Centre for Excellence in HIV/AIDS. Therapeutic guidelines antiretroviral treatment of adult HIV infection. February 2009. 21 British Columbia Centre for Excellence in HIV/AIDS. Therapeutic guidelines antiretroviral treatment of adult HIV infection. January 2011. 22 Thompson MA, Aberg JA, Cahn P et al. Antiretroviral treatment of adult HIV infection 2010 recommendations of the international AIDS society-USA panel. JAMA 2010; 304: 321–333. 23 Hammer SM, Eron JJ Jr, Reiss P et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA [Consensus Development Conference Practice Guideline Research Support, Non-U.S. Gov’t]. 2008; 300: 555–570. 24 British Columbia Centre for Excellence in HIV/AIDS. Therapeutic guidelines antiretroviral treatment of adult HIV
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infection. February 2013. Available at http://www.cfenet.ubc .ca/therapeutic-guidelines/adult (accessed 1 May 2014). 25 Thompson MA, Aberg JA, Hoy JF et al. Antiretroviral treatment of adult HIV infection 2012 recommendations of the international antiviral society-USA panel. JAMA 2012; 308: 387–402. 26 Patterson S, Cescon A, Samji H et al. Cohort profile: HAART observational medical evaluation and research (HOMER) cohort. Int J Epidemiol 2014; 1: doi: 10.1093/ije/dyu046. 27 Hogg RS, Yip B, Chan KJ et al. Rates of disease progression
33 CATIE. Routine HIV testing in acute care: Vancouver STOP project. Vancouver 2013; Available at http://www.catie.ca/en/pc/program/acute-care. 34 British Columbia Centre for Disease Control. HIV testing guidelines for the province of British Columbia 2014. 2014. Available at
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ORIGINAL RESEARCH
Declines in highly active antiretroviral therapy initiation at CD4 cell counts ≤ 200 cells/μL and the contribution of diagnosis of HIV at CD4 cell counts ≤ 200 cells/μL in British Columbia, Canada L Lourenço,1 H Samji,1 A Nohpal,1 W Chau,1 G Colley,1 K Lepik,1 R Barrios,1 V Lima,1,2 RS Hogg,1,3 JSG Montaner,1,2 S Kesselring1 and DM Moore1,2 1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada, 2Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada and 3Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada Objectives
The aim of the study was to examine trends in initiating highly active antiretroviral therapy (HAART) with a CD4 count ≤ 200 cells/μL and the contribution of having a CD4 count ≤ 200 cells/μL at the time of diagnosis to these trends, in British Columbia (BC), Canada. Methods
We included in the analysis treatment-naïve BC residents aged ≥ 19 years who initiated HAART from 2003 to 2012. Participants were classified as follows: Group 1: diagnosed and initiated HAART with a CD4 count > 200 cells/μL; Group 2: diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL; and Group 3: diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL. We measured trends in initiating HAART with a CD4 count ≤ 200 cells/μL and used logistic regression models to measure factors associated with initiating HAART with a CD4 count ≤ 200 cells/μL, stratified by having a CD4 count ≤ 200 cells/μL or > 200 cells/μL at the time of diagnosis. Results
Between 2003 and 2012, 3506 BC residents initiated HAART. Of these, 44% (1558 of 3506) initiated HAART with a CD4 count ≤ 200 cells/μL. This proportion declined from 69% (198 of 287) in 2003 to 21% (81 of 330) in 2012 (P < 0.001). The proportion of those in Group 3 increased from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2012 (P < 0.001). Overall, 56% (1948), 22% (776) and 22% (782) made up Groups 1, 2, and 3, respectively. In adjusted analyses, seeing a specialist was significantly associated with being in Group 3. Using injection drugs and seeing a specialist were associated with being in Group 2. Conclusions
In recent years, among individuals who ever initiated HAART in BC, being diagnosed with low CD4 cell counts has become a greater contributor to initiating HAART with low CD4 cell counts. Keywords: diagnosis, highly active antiretroviral therapy, HIV, late initiation, late presentation. Accepted 9 October 2014 to a chronic, manageable condition. HAART acts to reduce viral load in the blood with the benefit of delaying the progression of HIV/AIDS and mortality associated with it [1–5], allowing individuals to live near-normal lifespans [6]. In addition, HAART has been shown to be highly effective in the prevention of HIV transmission [7,8]. However, the benefits of HAART, at both the individual and the societal level, are reduced among
Introduction Highly active antiretroviral therapy (HAART) has dramatically transformed HIV infection from a fatal disease Correspondence: Lillian Lourenço, Epidemiology and Population Health Program, British Columbia Centre for Excellence in HIV/AIDS, 680–1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel: (604) 682 2344 Ext. 66275; fax: (604) 806 9044; e-mail: [email protected]
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individuals who initiate treatment late in the course of their illness [1]. Late HAART initiation, typically defined as starting treatment with a CD4 cell count of ≤ 200 cells/μL, has been shown to limit the therapeutic benefit of HAART and is associated with an increased risk of both AIDS- and nonAIDS-related clinical events and mortality [3,9–16]. The UK Collaborative HIV Cohort Study estimates that life expectancy decreases by over 10 years in individuals initiating antiretroviral therapy with CD4 cell counts < 200 cells/μL compared with individuals starting at 200 to 350 cells/μL [10]. Furthermore, late HAART initiation has been found to be associated with impaired CD4 recovery [1,17,18] and a reduced likelihood of achieving virological suppression [15,16]. HIV treatment recommendations on when to initiate HAART have changed over time. In 1996, when HAART first became available, physicians offered HAART regardless of CD4 cell count. In 2000, with growing concerns about HAART-related toxicities and side effects, as well as the emerging threat of HIV drug resistance, the International Antiviral Society-USA (IAS-USA) HIV treatment guidelines recommended delaying HAART initiation among asymptomatic patients, until CD4 cell counts declined to ≤ 200 copies/μL [19]. Over time, starting in 2002, with increasing awareness and understanding of the harmful effects of late HAART initiation and treatment interruptions coupled with the increasing availability of safer, simpler and better tolerated regiments, the IAS-USA guidelines moved to recommend HAART initiation at higher CD4 cell counts, to < 350 cells/μL in 2008, and to ≤ 500 cells/μL in 2010 [20–23]. More recently, IAS-USA guidelines recommend that HAART be offered to all HIVinfected persons regardless of CD4 cell count, except for elite controllers [24,25]. Treatment guidelines in BC have remained consistent with those of the IAS-USA since 1996. We examined trends in initiating HAART with a CD4 cell count of ≤ 200 cells/μL among BC residents from 2003 to 2012 and investigated characteristics of these individuals. Furthermore, we examined trends in the contribution of being diagnosed with a CD4 cell count ≤ 200 cells/μL to initiating HAART with a CD4 cell count ≤ 200 cells/μL in this population.
Methods We conducted a retrospective cohort analysis of all individuals enrolled in the HAART Observational Medical Evaluation and Research (HOMER) cohort who initiated HAART between 1 January 2003 and 31 December 2012 [26]. The HOMER cohort is made up of individuals in the British Columbia HIV/AIDS Drug Treatment Program (DTP) who: (i)
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were ≥ 19 years of age at the time of HAART initiation, (ii) started the program antiretroviral therapy-naïve, (iii) were on two nucleosides/nucleotides alongside either a protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted PI, (iv) had a baseline CD4 count and plasma viral load (pVL) measurement conducted within 6 months prior to antiretroviral initiation, and (v) for those who initiated HAART between 1 January 2003 and 31 December 2010, had a baseline pVL > 5000 copies/mL; for those who initiated HAART between 1 January 2011 and 31 December 2012, had a baseline pVL > 50 copies/mL. Further details of the HOMER cohort have been previously described [27,28]. The BC Centre for Excellence in HIV/AIDS (BC-CfE) has been responsible for the distribution of HAART at no cost for all eligible BC residents since 1992 [27]. The BC-CfE’s DTP has received ethical approval from the University of British Columbia Ethics Review Committee at the St Paul Hospital site. In order for individuals to enroll in the DTP, their physicians must complete a drug request form which acts as a legal prescription. These forms collect patient demographic information as well as CD4 cell counts, hepatitis serology, some HIV-risk behaviour data, and HAART treatment history. Prescriptions are renewed every one to three months. All pVL testing conducted in BC is performed at the St Paul’s Hospital Virology Laboratory using the Roche Amplicor Monitor assay (Roche Diagnostics, Laval, Quebec, Canada) by either the standard method or the ultrasensitive adaptation. CD4 cell counts are measured by flow cytometry, followed by fluorescent monoclonal antibody analysis (Beckman Coulter, Inc., Mississauga, Ontario, Canada). Approximately 85% of all CD4 testing performed in BC is performed at St Paul’s Hospital in Vancouver. These laboratory data are captured by regular linkages with the laboratory database and that of the DTP registry. CD4 cell counts that are not captured through the laboratory data linkage are obtained through the prescription forms.
Study design and statistical analyses We categorized our study population into three groups: (i) those who were diagnosed with a first-ever CD4 cell count > 200 cells/μL and had a CD4 cell count > 200 cells/μL at the time of HAART initiation (diagnosed and initiated HAART with a CD4 count > 200 cells/μL); (ii) those who were diagnosed with a first-ever CD4 cell count > 200 cells/μL and had a CD4 cell count ≤ 200 cells/μL at the time of HAART initiation (diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL), and (iii) those who were diagnosed with a first-ever CD4 cell count ≤ 200 cells/μL and had a CD4 cell
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count ≤ 200 cells/μL at the time of HAART initiation (diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL). As we did not have HIV diagnosis date data, we made several assumptions when assembling these three groups in instances when it was not clear whether the available CD4 cell count was an individual’s first-ever CD4 cell count: (i) HOMER participants with an available baseline CD4 cell count but lacking a first-ever CD4 cell count were excluded from the analysis if a VL measurement was performed prior to their baseline VL measurement (n = 135), because it could not be safely assumed that the baseline CD4 count was their first-ever CD4 cell count. Of these individuals, 79% were male, and they had a median age of 44 years (25th−75th percentile 36–51 years) and a median baseline CD4 cell count of 120 (25th–75th percentile 40–170) cells/ μL; (ii) If a participant only had a baseline CD4 count available and no other previous CD4 counts or VL results, then it was assumed that this was the individual’s first CD4 count and, if that CD4 count was ≤ 200 cells/μL, the individual was considered to be in the ‘diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’ group (n = 200). (iii) DTP participants who had a baseline CD4 count ≥ 200 cells/μL and no evidence of prior pVL or CD4 count measurement were assumed to have been diagnosed early (n = 145). (iv) Those who had a baseline CD4 count ≥ 200 cells/μL with no available first CD4 count but an available first pVL (which corresponded in time with the baseline CD4 count) were classified as ‘diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ (n = 158). We examined trends in the proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL and the contribution of being diagnosed with a CD4 count ≤ 200 cells/μL over a 10-year period (2003–2012), using the Cochran−Armitage test of trend. We also conducted a sensitivity analysis using a CD4 count threshold of ≤ 350 cells/μL at the time of diagnosis and HAART initiation. We conducted bivariable analyses of sociodemographic, clinical, and laboratory variables, comparing those in the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL with: (i) those in the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those in the group who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL. In addition, we compared two physician-related variables (i): service provider group (specialist vs. nonspecialist), which describes whether the physician who prescribed the first-ever HAART prescription was a specialist or not, and (ii) ‘physician experience’, which was defined as the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual over the
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preceding 2 years. Categorical variables were compared using the Fisher exact test and continuous variables were compared using the Wilcoxon rank-sum test. Finally, two logistic regression models were developed. We modelled how (i) those in the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those in the group who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL, differed from those in the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL. Univariate logistic regression models were used to identify variables associated with these models. Variables with P < 0.05 in the univariate analyses were candidates for inclusion in the final possible multivariate logistic regression model. A backward stepwise technique was used in the selection of covariates to build these models [29]. To minimize the potential for collinearity, we assessed correlation between pairs of independent variables. The selection of variables was based on two criteria: the Akaike information criterion (AIC) and Type III P-values. All analyses were performed using SAS software version 9.3 (SAS Institute, Cary, NC).
Results Between 1 January 2003 and 31 December 2012, a total of 3506 antiretroviral therapy-naïve HIV-positive individuals 19 years of age or older initiated HAART and were eligible for study analysis. Of these, 81.5% were male and the median age was 42 years (25th–75th percentile 35 to 49 years) at the time of HAART initiation. A total of 20% (696) had a reported history of injecting drug use (IDU), 17% (596) were men who had sex with men (MSM), 7% (260) of study participants were identified as having heterosexual exposure to HIV, and 56% (1954) had either no risk category information, were infected by either blood transfusion or perinatal exposure, or were categorized as having an unknown risk (i.e. risk factor not identified). Overall, 44% (1558) of eligible study individuals initiated HAART with CD4 cell counts ≤ 200 cells/μL. The proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL declined over the study period from a high of 69% (198 of 287) starting late in 2003 to a low of 21% (81 of 386) in 2012 (Fig. 1; P < 0.001 for test of trend). When categorized on the basis of CD4 cell counts at diagnosis and HAART initiation, 56% (1948 of 3506) were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, 22% (776 of 3506) were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL, and 22% (782 of 3506) were diagnosed and initiated HAART with a CD4 count > 200 cells/μL (Table 1). An additional 14 individuals
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Fig. 1 Number of highly active antiretroviral therapy (HAART)-naïve individuals initiating HAART with a CD4 cell count ≤ 200 cells/μL and diagnosed with a CD4 cell count ≤ 200 cells/ μL from 2003 to 2012 in British Columbia, Canada. *The proportion of indiviudals initiating HAART with a CD4 cell count ≤ 200 cells/μL among those who initiated HAART. **The proportion of individuals diagnosed with a CD4 cell count ≤ 200 cells/μL among those who initiated HAART late with a CD4 cell count ≤ 200 cells/μL.
(0.3%) had at least one CD4 cell count ≤ 200 cells/μL prior to HAART initiation, but their most recent CD4 cell count prior to starting HAART was > 200 cells/μL. These individuals were excluded from further analyses. Among those who initiated treatment with a CD4 count ≤ 200 cells/ μL, the proportion with a CD4 count ≤ 200 cells/μL at diagnosis increased over the study period from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2013 (P < 0.001 for test of trend). Our sensitivity analysis found that 52% (150 of 287) of participants initiated HAART with a CD4 count ≤ 350 cells/μL in 2003 and 28% (110 of 380) initiated HAART with a CD4 count ≤ 350 cells/μL in 2012 (P < 0.001 for test of trend). Similarly, among those who initiated treatment with a CD4 count ≤ 350 cells/μL, the proportion of those diagnosed with a first CD4 count ≤ 350 cells/μL increased over time from 56% in 2003 to 65% in 2013 (P < 0.001 for test of trend). The median CD4 count at the time of HAART initiation from 2008 to 2012 was 200 cells/μL (25th−75th percentile 80–290 cells/μL). Baseline characteristics of our study population, comparing those who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL with (i) those who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL and (ii) those who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL, are summarized in Table 1.
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In our multivariate logistic regression models, we included an IDU risk variable (yes/no/unknown) instead of the risk category variable because the risk category variable had over 50% unknown data and the IDU risk variable had the least amount of missing data. In the multivariate logistic regression model comparing the group who were diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL with the group who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, we found that having a history of IDU [adjusted odds ratio (aOR) 2.73; 95% confidence interval (CI) 2.23–3.35] and seeing a physician with less HAART prescribing experience (aOR 1.06; 95% CI 1.03–1.09) were independently associated with being diagnosed with a CD4 count > 200 cells/μL and initiating HAART with a CD4 count ≤ 200 cells/μL (Table 2, model 1). Seeing a specialist was found to be approaching statistical significance (aOR 1.20; 95% CI 1.00–1.44). However, having an unknown Aboriginal ethnicity was associated with having a reduced odds of initiating HAART with a CD4 cell count ≤ 200 cells/μL (aOR 0.71; 95% CI 0.58−0.88). Comparing those who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL with those who were diagnosed and initiated HAART with a CD4 count > 200 cells/μL, we found that having a specialist prescribe an individual’s first HAART regimen (aOR 2.77; 95% CI 2.30–3.33) was independently associated with being
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Table 1 Bivariate analyses comparing individuals who were diagnosed and initiated highly active antiretroviral therapy (HAART) with a CD4 cell count > 200 cells/μL with individuals who were: (i) diagnosed with a CD4 cell count > 200 cells/ μL and initiated HAART with a CD4 cell count ≤ 200 cells/ μL and (ii) diagnosed and initiated HAART with a CD4 count cell count ≤ 200 cells/ μL
Variable Gender [n (%)] Female Male Ethnicity [n (%)] Aboriginal Non-Aboriginal Unknown Hepatitis C [n (%)] Positive Negative Unknown AIDS diagnosis [n (%)] Yes No HIV risk factors [n (%)] Heterosexual IDU MSM Other/unknown Service provider group* [n (%)] Specialist Nonspecialist Age at HAART initiation (years) Median (25th-75th percentile) Baseline viral load (log10 copies/ml) Median (25th-75th percentile) Time between first plasma viral load and HAART initiation (years)† Median (25th-75th percentile) Physician experience‡ Median (25th-75th percentile)
Total n (%)
Diagnosed and initiated HAART with a CD4 count > 200 cells/μL n = 1948
Diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL n = 776
649 (19) 2857 (81)
342 (18) 1606 (82)
155 (20) 621 (80)
0.153
152 (19) 630 (81)
0.249
414 (12) 1115 (32) 1977 (56)
197 (10) 553 (28) 1198 (62)
114 (15) 289 (37) 373 (48)
< 0.001
103 (13) 273 (35) 406 (52)
< 0.001
1246 (36) 2029 (58) 231 (7)
575 (30) 1235 (63) 138 (7)
391 (50) 342 (44) 43 (6)
< 0.001
280 (36) 452 (58) 50 (6)
0.006
478 (14) 3028 (86)
103 (5) 1845 (95)
120 (15) 656 (85)
< 0.001
255 (33) 527 (67)
< 0.001
260 (7) 1217 (35) 646 (18) 1383 (39)
125 (6) 333 (17) 360 (18) 1130 (58)
44 (6) 196 (25) 117 (15) 419 (54)
< 0.001
91 (12) 167 (21) 119 (15) 405 (52)
< 0.001
1788 (51) 1718 (49)
837 (43) 1111 (57)
411 (15) 365 (47)
< 0.001
540 (69) 242 (31)
< 0.001
42 (35–49) 4.91 (4.44–5.00)
41 (34–49) 4.71 (4.26–5.00)
42 (35–48) 5.00 (4.69–5.00)
1 (0–4)
2 (0–4)
3 (1–6)
126 (47–277)
139 (58–283)
116 (41–286)
P1
0.373 < 0.001
< 0.001 0.018
Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL n = 782
43 (37–50) 5.00 (4.85–5.18)
P2
< 0.001 < 0.001
1 (0–2)†
< 0.001
87 (38–244)
< 0.001
*The type of service provider who provided the first-ever HAART prescription. †Time between first plasma viral load and treatment initiation for individuals in the ‘Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’ group is reported in months. ‡Physician experience refers to the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual, over the preceding 2 years (per 100 patients). P1 represents the p-value between the groups ‘Diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ and ‘diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL’. P2 represents the p-value between the groups ‘Diagnosed and initiated HAART with a CD4 count > 200 cells/μL’ and ‘diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL’. Hepatitis C, history of having an antibody positive Hepatitis C test; IDU, history of injection drug use; MSM, Men who have sex with men.
diagnosed and initiating HAART with a CD4 count ≤ 200 cells/μL (Table 2, model 2). Having an unknown Aboriginal ethnicity was associated with having a reduced odds of initiating HAART with a CD4 count ≤ 200 cells/μL (aOR 0.78; 95% CI 0.64–0.97). Having a physician with less HAART prescribing experience was approaching statistical significance for having increased odds of being diagnosed and initiating HAART with a CD4 count ≤ 200 cells/μL (aOR 0.97; 95% CI 0.95–1.00).
Discussion Our results demonstrate that the number and proportion of antiretroviral therapy-naïve individuals initiating
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HAART with a CD4 count ≤ 200 cells/μL declined significantly from 69% in 2003 to 21% in 2013. In addition, the absolute number of individuals initiating HAART with a CD4 count ≤ 200 cells/μL also declined from 198 in 2003 to 81 in 2013. These results are comparable to results from other HAART distribution programmes in industrialized countries, which have ranged from 23% to 65% [12,16,30,31]. In addition, we showed that, among individuals who initiated HAART, the contribution of being diagnosed with a CD4 count ≤ 200 cells/μL to the proportion of individuals initiating HAART with a CD4 count ≤ 200 cells/μL increased over the study period from approximately 49% in 2003 to over 69% in 2012.
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Table 2 Multivariable logistic regression model comparing those who initiated highly active antiretroviral therapy (HAART) with a CD4 cell count ≤ 200 cells/ μL with those who initiated with higher CD4 cell counts stratified on the basis of CD4 cell count at HIV diagnosis
Variable Gender Male Female Ethnicity Non-Aboriginal Aboriginal Unknown Injecting drug user history No Yes Unknown Service provider group* Nonspecialist Specialist Age at HAART initiation (per decade) Physician experience†
Model 1
Model 2
Diagnosed and initiated HAART with a CD4 count > 200 cells/μl versus Diagnosed with a CD4 count > 200 cells/μL and initiated HAART with a CD4 count ≤ 200 cells/μL
Diagnosed and initiated HAART with a CD4 count > 200 cells/μL versus Diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
P
1.00 1.17 (0.95–1.45)
0.141
1.00 1.11 (0.85–1.45) 0.60 (0.50–0.72)
< 0.001
1.00 0.85 (0.63–1.13) 0.71 (0.58–0.88)
1.00 2.59 (2.14–3.13) 0.95 (0.75–1.20)
< 0.001
1.00 1.50 (1.27–1.77) 1.03 (0.95–1.12)
< 0.001
1.05 (1.03–1.08)
Unadjusted OR (95% CI)
P
NS
Adjusted OR (95% CI)
P
P
1.00 1.13 (0.92–1.40)
0.249
NS
0.006
1.00 1.06 (0.80–1.40) 0.69 (0.57–0.83)
< 0.001
1.00 0.97 (0.71–1.31) 0.78 (0.64–0.97)
0.052
1.00 2.73 (2.23–3.35) 1.18 (0.91–1.53)
< 0.001
1.00 1.20 (1.00–1.44) 0.46 (0.36–0.58)
< 0.001
1.00 1.15 (0.94–1.41) 0.58 (0.44–0.76)
< 0.001
0.053
1.00 2.96 (2.48–3.53) 1.21 (1.12–1.31)
< 0.001 < 0.001
1.00 2.77 (2.30–3.33) 1.21 (1.11–1.31)
< 0.001
0.425
1.00 1.20 (1.00–1.44) NS
< 0.001
1.06 (1.03–1.09)
< 0.001
1.01 (0.98–1.04)
0.41
0.97 (0.95–1.00)
0.060
< 0.001
OR, odds ratio; CI, confidence interval; *Service Provider Group: The type of service provider who provided the first-ever HAART prescription. †Physician experience refers to the number of individuals the first-ever HAART prescribing physician had previously treated, prior to a given individual, over the preceding 2 years (per 100 patients). NS, not selected.
Our results imply that modifications to HAART guidelines and other efforts to promote earlier initiation of HAART have been effective. However, it also highlights the need to improve timely diagnosis of HIV infection in BC. This is especially true in the context of treatment as prevention programmes which rely on timely HIV diagnosis and HAART initiation to ensure programme success. Our finding that diagnosis with a CD4 count ≤ 200 cells/μL has become a greater contributor to initiating HAART at very low CD4 cell counts suggests that increased routine testing is necessary to uncover the undiagnosed population during the early stage of their HIV disease. HIV testing guidelines which recommend increased universal testing in primary care, such as those from the US Centers for Disease Control and Prevention [32], may aid in earlier diagnosis of these individuals. In 2011, a pilot programme which introduced routine HIV testing in hospitals and in primary care clinics was implemented in the city of Vancouver, BC [33]. The programme has observed a dramatic increase in HIV testing rates, with high acceptance by patients. This intervention resulted in an additional 40 HIV diagnoses, in patients who were not likely to have been otherwise offered a test for diagnosis (as indicated by the number of medical care visits prior to diagnosis). The results of this present study and the
© 2015 British HIV Association
above-mentioned pilot study support the recent implementation of new HIV testing guidelines in BC which recommend additional routine testing in health care settings, even for patients without identifiable risk factors for HIV infection [34]. Our finding that individuals who were diagnosed and initiated HAART with a CD4 count ≤ 200 cells/μL were more likely to have received a first HAART prescription from a specialist vs. a nonspecialist probably does not mean that specialists are more likely to delay treatment initiation. Rather, it suggests that specialists are more likely to see patients who have advanced HIV disease. Indeed, in our study sample, 69% of individuals diagnosed late were treated by a specialist. This does suggest that the pool of referrals from which physicians refer to a specialist is more likely to have individuals who are either not engaged in care or diagnosed with HIV infection late in the course of their illness. This observation warrants further investigation. We found a weak association between physicians with less HAART prescribing experience and initiating HAART with a CD4 count ≤ 200 cells/μL. This finding suggests that physicians with less HIV care experience may benefit from enhanced support from more experienced HIV-treating physicians. We did perform a subanalysis to explore
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Declines in late HAART initiation 343
whether or not a threshold could be determined which would indicate the target physician population who would benefit from such an intervention (data not shown). However, we did not find that such a threshold existed. Still, efforts should be made to improve support for those physicians with less HAART prescribing experience. We found that persons with a history of IDU were more likely to be diagnosed with a CD4 cell count > 200 cells/μL and to initiate HAART with a CD4 count ≤ 200 cells/μL. This result probably reflects the difficulty in engaging persons with a history of IDU in effective care [35]. It may also reflect physician unwillingness to initiate people who use injection drugs on HAART because of concerns regarding HAART adherence and possible subsequent development of HAART resistance mutations [35–38]. Continuing professional development regarding HAART use and engaging marginalized populations in care may help in this regard. It is worth noting that several studies have demonstrated that physicians have poor predictive ability with respect to levels of adherence among people who inject drugs [37,39] and most injection drug users will achieve satisfactory outcomes when on HAART [35]. Our study had several limitations. First, the DTP database does not systematically collect HIV diagnosis dates. Therefore, we used the first-ever recorded CD4 cell count date as a proxy for HIV diagnosis date. This is a reasonable assumption in our setting, as most patients who receive an HIV diagnosis would be offered a viral load and CD4 cell count measurement at the next follow-up visit, at no cost. Secondly, our analysis was limited to only those individuals who ever initiated HAART and did not include those who never initiated HAART. This limits the generalizability of our results. However, given the universal accessibility of health care and HIV treatment in BC, we feel that the number of individuals who are diagnosed with HIV infection and who do not eventually receive ART is probably quite small. Indeed, an analysis using BC vital statistics data which included all HIV-positive individuals, regardless of whether or not they had ever accessed ART, found that the number of HIV-related deaths in BC decreased from 127 individuals in 2003 to 59 in 2011 (this corresponds to a decrease in the mortality rate from 3.1 to 1.3 from 2003 to 2011), suggesting that very few individuals are dying from HIV infection in BC without ever accessing ART [40]. Thirdly, there were a large number of unknowns in the HIV risk and ethnicity categories. This limited our ability to carry out further risk-based stratifications. In conclusion, our analysis provides valuable insight into trends in initiating HAART with a CD4 cell count ≤ 200 cells/μL in BC and the contribution of being diagnosed at very low CD4 cell counts to these trends. Our results demonstrate that initiating HAART at very low CD4
© 2015 British HIV Association
cell counts is becoming less common but also highlights that having CD4 cell counts ≤ 200 cells/μL at the time of diagnosis is rapidly becoming the main determinant of initiating HAART at very low CD4 cell counts. This highlights the need to improve strategies to diagnose HIVinfected individuals much earlier in the course of their HIV infection. In this regard, the recent adoption of routine HIV testing guidelines in BC represents a very favourable development.
Acknowledgements We thank the participants in the BC HIV/AIDS Drug Treatment Program and the physicians, nurses, social workers and volunteers who support them. Conflicts of interest: This study received limited unrestricted funding from Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. The funding provided by the commercial sources has been directed to the institution and not to the investigators. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the HIV Medicine policies on sharing data and materials. Sources of support: DMM is supported by a Scholar Award from the Michael Smith Foundation for Health Research. JSGM is supported by the British Columbia Ministry of Health and by the US National Institutes of Health (1DP1DA026182 and R01DA036307). He has also received limited unrestricted funding from Abbvie, BristolMyers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. VDL is supported by a Scholar Award from the Michael Smith Foundation for Health Research, a New Investigator Award from CIHR and two grants from the Canadian Institutes of Health Research (MOP-125948) and the US National Institute on Drug Abuse (R03DA03385101). The funders had no role in the design, data collection, data analysis, data interpretation, or writing of the report. The remaining authors report no disclosures. Author contributions: LL, HS, DM, KL, BH, VDL, JSGM and GC contributed to the conception and design of the study. AN, GC and WC performed all statistical analyses. LL and DM drafted the manuscript. DM and JSGM advised on all aspects of the study. All authors revised the manuscript critically and approved the final version submitted for publication.
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