Regional differences in rates of HIV-1 viral load monitoring in Canada: Insights and implications for antiretroviral care in high income countries

Viral load (VL) testing is an essential component of the care of HIV-positive individuals, both with regard to timing of initiation of antiretroviral therapy (ART) and to monitoring of virologic response to combination ART (cART) [1]. The goal of cART is sustained virologic suppression, defined as a VL below the level of detection of the test performed [1]. Guidelines recommend that HIV-positive individuals receive VL testing at intervals of three to four months as standard of care [1]. CD4 count monitoring is important for deciding when to start cART and for determining prognosis, but alone is insufficient as a marker of treatment efficacy as it does not identify individuals experiencing virologic rebound or failure [2]. Early determination of virologic rebound and failure is one of the most crucial components of HIV management as it contributes to the reduction of ART drug resistance [3]. Lastly, VL monitoring has also been shown to promote treatment adherence, which is additionally important for maintaining virologic suppression and reducing the evolution of drug resistance [4].

Access to VL testing has been studied previously. In an Ontario cohort, injection drug use, younger age and residence in Toronto were associated with lower VL testing rates [5]. In another study, drug users were also found to be at risk for irregular VL monitoring [6]. In a study of individuals who initiated ART between 1994 and 2000, individuals with low CD4 counts and high VLs had the highest rates of laboratory testing [7].

In this study, we examine whether there are regional differences in patterns of VL testing among individuals who initiated cART therapy since January 1, 2000 in Canada, where VL testing is available without charge to all HIV-positive residents as part of the provincial universal health insurance plans. Furthermore, we identified demographic and clinical factors associated with suboptimal frequency of VL testing.

The Canadian Observational Cohort (CANOC) collaboration is a Canadian cohort study of antiretroviral naïve HIV-positive patients initiating cART since January 1^st 2000. The study was established in March 2008 with funding from the Canadian Institutes of Health Research (grant# 711098) and the CIHR Canadian HIV Trials Network (CTN242) and includes cohorts and investigators from across the country (listed at the end of the manuscript). The collaboration is open to all Canadian HIV treatment cohorts with more than 100 eligible patients.

There was considerable regional variation in annual rates of VL measurement documented in this Canada-wide study. This variation remained significant even after adjusting for demographic variables such as age and HIV risk factors and clinical variables such as year of cART initiation, type of cART regimen, being in the first year of cART, AIDS-defining illness and whether or not the previous VL was below the limit of detection. In Ontario and Quebec, VL was measured quarterly on average. In BC, rates of VL measurement were even more frequent than guidelines suggest, with an average measurement frequency of almost five times annually.

There are a number of possible explanations for the regional differences in rates of viral load measurement. Some of the difference in measurement rate was due to regional differences in demographic factors such as the proportions of IDUs, who typically have less frequent viral load testing, or pregnant women, in whom viral load is monitored more closely. Further differences could be due to variation in rates of VL blips among regions, after which a repeat VL measurement is typically ordered. Recent data has documented differing rates of blips by VL assay [10, 11] and this may explain the higher rates of testing in BC. Regional differences in VL testing policies may also have an impact. While there are no differences among provinces in the official guidelines for the frequency of VL measurement, it is possible that there are differences in the implementation of the guidelines. In Ontario, a VL will not be performed by the laboratory if one has been done within the last 14 days. Furthermore, rates of VL measurement may be higher in British Columbia due to the fact that all antiretroviral drug distribution and VL testing is coordinated through a single center in the province. Lastly, differences in participation rates among provinces in research studies, which may require more frequent VL testing may explain some of regional variation.

Effective therapy should result in at least a 90% or 10-fold (1.0 log₁₀ copies/mL) decrease in plasma VL in the first month and suppression to below 50 copies/mL by 24 weeks, depending on the pretreatment VL level [1]. Current guidelines suggest once VL suppression to below 50 copies/mL is confirmed, it should be assessed at regular intervals (e.g. every 3 or 4 months). Isolated episodes of low-level viremia ("blips") are not necessarily predictive of subsequent virologic failure, but consistent elevations of VL above 50 copies/mL meet a strict definition of virologic failure. Emergence of a detectable VL in a previously suppressed patient (i.e. previously consistently < 50 copies/mL) mandates re-evaluation of the case, including repeated testing to confirm whether this represents a "blip" or virologic failure. Confirmed VL rebound should prompt a careful evaluation of regimen tolerability, drug-drug interactions, resistance and patient adherence. CD4+ cell counts should generally be assessed in concert with VL.

In terms of the demographic findings, our findings are similar to those of the study conducted in Ontario several years ago and could likely be generalizable to other settings with universal health care programs. In settings with user-pay programs for virologic monitoring, it seems likely that socioeconomic factors will have a considerably greater influence on rates of testing. In resource limited settings, availability and travel distances are likely to remain significant barriers to regular monitoring of VL levels.

Our results have important implications for guidelines and for research into the monitoring of VL. For patients for whom VL is measured less frequently, virologic rebound will be detected later on average and patients will remain on failing regimens longer than is necessary. In some circumstances, however, it is safe to measure VL less frequently [12]. A reduced monitoring schedule would result in cost savings due to both the cost of the laboratory testing and the cost of the physician time. As ART is a life-long commitment, cost considerations are not insignificant. Further, less frequent VL monitoring would reduce the inconvenience to the patient, which may improve overall compliance. However, while it may be safe and cost effective to extend the period between VL measurements from three to six months in patients with virologic suppression, periods in excess of nine months are less easily justified and place patients at unnecessary risk. Steps should be taken to facilitate more careful VL monitoring in groups at high risk for gaps in testing.

A strength of our study is that VL monitoring is provided free of charge to all HIV-positive individuals in Canada, so that we were able to examine correlates of rates of VL testing in the absence of financial barriers to testing. Further, by combining data from nine sites across Canada, we achieved a large sample size as well as a good representation by region, gender, race, and other demographic characteristics. CANOC represents about a quarter of all HIV-positive people in the country who are currently on ART and approximately half of those who have initiated on more modern regimens since 2000 [13]. This is the largest sample of HIV-positive people on ART compiled in Canada and represents one of the most representative samples put together in a high-income country. One limitation of this dataset is that this information is not currently available on a nation-wide basis, so regional differences in provinces other than BC, Ontario and Quebec could not be examined. A further limitation is that data were missing on race and HIV risk factors for many patients.

Future plans for investigation include further examination of the reasons for the regional differences in rates of VL testing. Also, an economic analysis to determine if the less frequent testing found in Ontario and Quebec is adequate in terms of clinical outcomes and could result in financial savings would be informative. Particularly, an analysis of VL testing frequency in patients with full virologic suppression where less testing may be adequate would be of interest and its impact on cost savings could be important.

In our setting, with universal health care and similar regional guidelines for viral load testing, significant variation in rates of VL measurement and the probability of a significant gap in testing were related to geographic region, age, HIV risk factors and clinical variables such as year of cART initiation, type of cART regimen, being in the first year of cART, AIDS-defining illness and whether or not the previous VL was below the limit of detection.