The dispensing of antiretroviral medications in British Columbia has been described in detail elsewhere.10,11
In brief, the HIV/AIDS Drug Treatment Program of the BC Centre for Excellence in HIV/AIDS remains the only source of free antiretroviral medications in the province, and less than 1% of HIV-infected British Columbians receive antiretrovirals from other sources.10
In June 1996 the Centre adopted antiretroviral therapy guidelines based on plasma viral loads, consistent with those put forward by the International AIDS Society-USA.12
The Centre's guidelines were revised in July 1997 to recommend triple-drug therapy for anyone with plasma HIV-1 RNA levels greater than 5000 copies/mL or CD4 cell counts below 500 cells/mL who had not previously received antiretroviral therapy.13
The Centre's HIV/AIDS Drug Treatment Program has received ethical approval from the University of British Columbia's Ethics Committee for Human Experimentation at its St. Paul's Hospital site, and the program conforms with the province's Freedom of Information and Protection of Privacy Act
All HIV-infected men and women in the current study were entered into the HIV/AIDS Drug Treatment Program when they received their first prescription for antiretroviral agents. Any physician enrolling an HIV-infected person must complete a drug request enrolment form, which acts as a legal prescription and supplies baseline information, including past HIV-specific drug history, CD4 cell count, plasma HIV-1 RNA level, current drug prescriptions and data about the enrolling physician. At the time of the first refill, participants are asked to complete a survey, which elicits information on sociodemographic characteristics. The treating physicians are also asked to complete a clinical staging form that uses the World Health Organization clinical staging system.14
Thereafter, participants complete annual surveys on a volunteer basis. In the present study, we evaluated all HIV-1 infected men and women who had not taken antiretrovirals previously and who were first prescribed triple-drug antiretroviral therapy between Aug. 1, 1996, and July 31, 2000. The patients were followed until Mar. 31, 2002.
As an initial analysis, we evaluated the baseline demographic and clinical characteristics of patients with and without a history of injection drug use. This variable was defined on the basis of self-reports (through the annual participant survey) and through physician reports. To be conservative in our analysis, we considered any positive report of this risk behaviour at any time during follow-up indicative of a history of injection drug use. The categorical explanatory variables described below were analyzed with Pearson's χ2 test, and continuous variables were analyzed with the Wilcoxon rank-sum test.
We then evaluated time to suppression of plasma HIV-1 RNA after initiation of the first HAART regimen. As previously,9,15
suppression was defined as the first of at least 2 consecutive measurements of plasma HIV-1 RNA level of less than 500 copies/mL. Those who never achieved suppression were censored at the date of the last measurement of HIV-1 RNA before Mar. 31, 2002. Patients who achieved an HIV-1 RNA level of less than 500 copies/mL only once were not considered to have achieved suppression and hence were not included in this analysis.
We also evaluated the time to rebound of plasma HIV-1 RNA after initial virological suppression below 500 copies/mL. This analysis included any patient who achieved at least one RNA measure below 500 copies/mL. As previously,15
rebound of HIV-1 RNA was defined as the first of 2 consecutive measurements of plasma HIV-1 RNA level of 500 copies/mL or more after any measurement of less than 500 copies/mL. To be conservative, the rebound event was assumed to occur at the midpoint date between the last HIV-1 RNA measurement of less than 500 copies/mL and the first of the 2 consecutive measurements at least 500 copies/mL. For consistency with previous studies we evaluated only patients who experienced RNA suppression before 32 weeks after the initiation of therapy.15
Patients who experienced suppression but not rebound were censored as of Mar. 31, 2002, or, if follow-up ended before this date, as of the last HIV-1 RNA measurement.
For the 2 treatment outcomes (suppression and rebound), cumulative event rates were estimated by Kaplan–Meier methods. Cox regression was then used to calculate univariate and adjusted relative hazards (RHs) and 95% confidence intervals (CIs).16
The assumption of proportional hazards was validated by inspection of log (–log [survival function]) estimates against log time plots. We derived population-based estimates for the overall cohort and then, in subanalyses, examined adherent patients only.
The following salient baseline prognostic variables were examined: date of initiation of therapy, adherence, sex, age, use of protease inhibitor in the initial HAART regimen, prior clinical diagnosis of AIDS, physician experience, CD4 cell count, and log10
-transformed plasma HIV-1 RNA level. We adjusted for the date of therapy initiation (on or after v. before July 31, 1997) in all multivariate analyses because this was the date when British Columbia's therapeutic guidelines for antiretroviral therapy were changed to recommend universal use of triple-drug regimens. The definition of adherence was based on the ratio of the period that the total amount of medication dispensed to the patient would last to the follow-up period during the first year on therapy, expressed as a percentage.17
We have previously demonstrated how this estimate strongly predicts virological response and mortality rate, and how it can be used to adjust for the potentially confounding effect of treatment interruption.9,18,19
Patients were defined a priori as nonadherent if they received antiretroviral medications for less than 95% of the follow-up period during the first year of therapy, as in previously published work.18
The definition of physician experience was also selected a priori on the basis of previous findings.20,21
For the multivariate analyses, we examined variables hypothesized a priori to be associated, either clinically or behaviourally, with virological response. These variables were first examined in univariate analyses to determine unadjusted RHs. Any variables associated with an event (suppression or rebound) in these univariate analyses (p
< 0.05) were then entered into a fixed model. In addition, initial HAART regimen, baseline HIV-1 RNA level and CD4 cell count were entered into the final model because of their known relation to clinical and virological response.11,22
All tests of significance were 2-sided, with a p
value of less than 0.05 indicating that an association was statistically significant.