Advances in the pharmacotherapy of HIV infection have resulted in important reductions in disease-related morbidity and mortality, mostly attributable to viral suppression and resultant immune reconstitution.1,2 However, immunologic discordance, in which an increase in CD4+ lymphocyte count does not accompany virologic suppression after the start of combination antiretroviral therapy (cART), has been reported in approximately 7%-36% of patients.3-9 Possible reasons contributing to the pathogenesis of this blunted CD4+ response include older age, poor thymic function, chronic T-cell activation, and ongoing HIV replication in lymphoid tissue.9-15 More recently, scarring of lymphoid tissue has been proposed as a potential physiologic explanation of a poor immunologic response in the context of sustained virologic suppression, as has altered Fas and Fas ligand pathway and cytokine production in bone marrow which may impact stem cell apoptosis.16,17 Although older age has consistently been shown to be a clinical correlate for immunologic discordance, other correlates are less consistently reported to be associated including lower nadir CD4+ count, lower baseline viral load, duration of HIV infection, intravenous drug use (IDU), hepatitis co-infection, and baseline CD4+ count (with both higher and lower baseline CD4+ count reported as significantly associated).4-12,18-28
In observational studies, the association between immunologic discordance and poor clinical outcomes has consistently been observed.4-12,18,21-36 However, very few studies have addressed the clinical impact of immunologic discordance in a population comprised exclusively of antiretroviral-naive patients.23,24 Furthermore, the definitions of a discordant immunologic response have generally been limited to assessment of the CD4+ count response at 12 months or less after the initiation of therapy.4-36 Recently a study set in a resource-constrained setting assessed the CD4+ count response at 6 months and found an association between discordant immunological response after cART and increased risk of death.36 It is noteworthy that many clinicians believe that CD4+ response is irrelevant provided full virologic suppression has been achieved.37
Finally, in many practice settings, antiretroviral-naive individuals are a growing proportion of the patient population. Thus, a better understanding of the long-term outcomes of immunologic discordance in this patient population is needed for informed management.
The purpose of our study was to assess the clinical implications of long-term immunologic discordance (ie, CD4+ count nonresponse) after the initiation of cART in antiretroviral-naive HIV-positive individuals. In this analysis, we assessed whether antiretroviral-naive HIV-positive individuals who attain full virologic suppression (<50 copies/mL), but incomplete immune response (CD4+ count <200 cells/mm3) at 1 and 2 years after cART initiation are at increased risk of death from all causes relative to those who achieve full virologic suppression with a more robust concordant CD4+ cell count recovery.
The Canadian Observational Cohort Collaboration (CANOC) is a population-based study of antiretroviral-naive HIV-positive patients initiating cART after January 1, 2000.38 The collaboration is open to all Canadian HIV treatment cohorts and currently includes 9 participating cohorts across Canada. Eligibility criteria for inclusion into CANOC are documented HIV infection, residence in Canada, aged 18 years and older, initiation of a first antiretroviral regimen comprised of at least 3 individual agents, and at least 1 measurement of HIV-1 RNA viral load and CD4+ cell count within 6 months of initiating cART. Patient selection and data extraction are performed locally at the data centers of the participating cohort studies. Non-nominal data from each cohort on a predefined set of demographic, laboratory, and clinical variables are then pooled and analyzed at the Project Data Centre in Vancouver, British Columbia. The last date of follow-up in the cohort for the current analysis was January 5, 2009. All participating cohorts have received approval from their institutional ethics boards to contribute non-nominal patient-specific data.
Study Participants Eligibility Criteria
Participants included in the current analysis were antiretroviral-naive individuals with a baseline viral load of >50 copies per milliliter, were first dispensed therapy with at least 3 individual antiretroviral agents on or after January 1, 2000, and achieved a viral load <50 copies per milliliter after the initiation of cART. For the assessment of outcomes after the first year of cART, participants must have had a viral load of <50 copies per milliliter on 2 sequential occasions and no viral load >50 copies per milliliter within the first year of initiating treatment, and a documented viral load <50 copies per milliliter and a CD4+ count measurement at 12 months after the start date of cART (window period of 9-15 months). Similarly, participants included in the 2-year analysis were required to have a viral load of <50 copies per milliliter on 3 sequential occasions and no viral load >50 copies per milliliter during the 2 years after which cART was started, and a documented viral load of <50 copies per milliliter and CD4+ count measurement at month 24 after the start date of cART (window period of 21-27 months).
Baseline characteristics were summarized using medians and interquartile ranges (IQR) for continuous variables and frequencies and proportions for categorical variables both for the 1-year and 2-year analyses.
The primary outcome of interest was time to death from all causes occurring after the time point when discordance was assessed (at 1 year and 2 years after the start of cART). Time was measured from cART initiation, but individuals with less than 1 year of follow-up were excluded from the 1-year analysis, and individuals with less than 2 years of follow-up were excluded from the 2-year analysis.
The primary correlate of interest was immunologic discordance at 1 and 2 years after the initiation of cART. Immunologic discordance was defined as a CD4+ count of <200 cells per cubic millimeter at 1 year and 2 years after cART initiation despite the attainment of a viral load <50 copies per milliliter. A CD4+ count within 9-15 months and 21 and 27 months after the initiation of cART was allowed for the 1 year and 2 years CD4+ count value, respectively. The comparator participants were classified as concordant responders if they had attained a viral load of <50 copies per milliliter and CD4+ cell count ≥200 cells per cubic millimeter at the 1-year and 2-year time points after the start of cART.
Kaplan-Meier curves were used to compare the time to death between discordant and concordant responders. Event-free subjects were censored at the last contact date or the first time the viral load rose >50 copies per milliliter after 15 months for the 1-year analysis and after 27 months for the 2-year analysis. Univariate Cox proportional hazards models were fit with the primary correlate and other baseline sociodemographic and clinical variables hypothesized to be associated with death based on previous literature.4-12,18-28 Furthermore, all covariates with a P value <0.10 in univariate models were considered for inclusion in the multivariable model. Separate models were constructed for the 1-year and 2-year analyses. When multiple covariates were likely to be collinear (eg, IDU and hepatitis C), the variable with the most statistical significance was chosen. Covariates with a significant effect (P < 0.05) remained in the final multivariable model.
A sensitivity analysis was carried out omitting participants with a baseline CD4+ cell count ≥200 cells per cubic millimeter to ensure that this patient population was not overly influencing the results. A further analysis was carried out and considered using time to AIDS-defining illness (ADI) or death as the primary outcome.
Univariate and multivariable logistic regression models were conducted to identify variables associated with immunologic discordance at 1 and 2 years after the initiation of cART. Variables which were significant at P < 0.10 in the univariate analyses were candidates for inclusion in the multivariable logistic regression model. When covariates were likely to be collinear, the variable with the most statistical significance was chosen. Only the correlates with a significant effect (P < 0.05) remained in the final multivariable model.
All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, NC).
A total of 4576 individuals initiated cART during the study period and 2028 and 1721 met the inclusion criteria for the 1-year and 2-year analyses, respectively. Individuals were excluded for various nonmutually exclusive reasons including: 322 due to ineligible cART regimens, 604 due to ineligible cART start dates, 334 due to inadequate follow-up, 169 due to baseline viral load being <50 copies per milliliter, and 1415 due to insufficient CD4+ count measurements at 1 year or 2 year.
The demographic and clinical characteristics of these study populations are summarized in Table 1. Immunologic discordance was observed in 19.9% (404 of 2028) and 10.2% (176 of 1721) of individuals at 1 and 2 years after the initiation of cART, respectively. For the 1-year analysis, the median durations of follow-up from the start of cART was 32 months (IQR: 21-49). For the 2-year analysis, the median duration of follow-up from the start of cART was 43 months (IQR: 32-57). A total of 49 deaths were observed after 1 year of cART [median 29 months after first year of cART (IQR: 18-44)], whereas 36 deaths were observed after 2 years of cART [median 44 months after second year of cART (IQR: 32-53)] (Table 1). In the same period of consideration, 8 and 7 ADIs were observed 1 year and 2 years after cART, respectively (Table 1).
Variables significantly associated with time to death after 1 and 2 years of cART by univariate and multivariable Cox regression analysis are summarized in Table 2. In the multivariable analysis, although age [adjusted hazard ratio (aHR) = 1.85 per decade, P < 0.001] and hepatitis C (aHR = 6.22, P < 0.001) remained significantly associated with mortality after 1 year of follow-up, 1 year immunologic discordance (CD4+ count < 200 cells/mm3) did not (aHR = 1.12; 95% CI: 0.54 to 2.30, P = 0.757) (Table 2). For the 2-year analysis, age (aHR = 2.01 per decade, P < 0.001), hepatitis C (aHR = 5.21, P < 0.001), year cART started (aHR = 0.75, P = 0.043), and 2-year CD4+ count <200 cells per cubic millimeter (aHR = 2.69; 95% CI: 1.26 to 5.78, P = 0.011) were significantly associated with mortality (Table 2). The sensitivity analysis restricting participants to those with a baseline CD4+ cell count ≤200 cells per cubic millimeter did not affect results in either the 1-year or 2-year analyses (data not shown). The additional investigation of time to ADI or death as the primary outcome did not alter the findings other than IDU being an additional correlate in the 2-year adjusted model (data not shown). The lack of impact adding ADIs to the primary outcome is likely related to their rare occurrence in the cohort.
Kaplan-Meier curves comparing the time to death between immunologic discordant and concordant responders are shown in Figure 1. A statistically significant difference was not observed in the 1 year after the initiation of cART (log rank P = 0.19). In contrast, clinical prognosis significantly worsened in immunologic discordant responders relative to concordant responders in the 2-year analysis (log rank P < 0.001).
In multivariable logistic regression models, variables associated with immunologic discordance at 1 year after the initiation of cART included age [(adjusted odds ratio (aOR) = 1.19 per decade, P = 0.015], IDU (aOR = 2.18, P < 0.001), baseline CD4+ count (aOR = 0.15 per 100 cells/mm3, P < 0.001) and and baseline viral load (aOR = 0.42 per log10 copies/mL, P < 0.001) (Table 3). Variables significantly associated with immunologic discordance in the 2-year analysis by multivariable logistic regression included age (aOR = 1.23 per decade, P = 0.023), male gender (aOR = 1.86, P = 0.022), IDU (aOR = 2.75, P < 0.001), and baseline CD4+ count (aOR = 0.24 per 100 cells/mm3, P < 0.001), and baseline viral load (aOR = 0.46 per log10 copies/mL, P < 0.001) (Table 3).
In our antiretroviral-naive patient population, long-term immunologic discordant response to initial cART (viral suppression without concomitant increase in CD4+ count) was associated with an increased risk of death. Although this association was not significant at 1 year after initiating cART, long-term immunologic discordance as measured at 2 years was associated with more than double the risk of mortality. This finding is consistent with a growing body of literature about the negative outcomes associated with discordant immunologic responses. It is particularly notable for HIV+ community members and their clinicians because it deals with the previously unstudied circumstances of antiretroviral-naive individuals and looks at the impact of CD4+ response after a longer period of time. Furthermore, we were able to confirm that older age, IDU, a lower baseline CD4+ count, and a lower baseline viral load were confirmed to be associated with immunologic discordance.
The lack of association between a discordant CD4+ count response at 1 year after the start of cART and mortality requires explanation. In a previous analysis that we conducted with a smaller sample size, we found that most of the clinical events in patients with a discordant immunologic response occurred within rather than after the first year of starting cART.40 This pattern suggests that a partial immune reconstitution is occurring in response to cART even in patients with limited CD4+ cell response and may be partially protective during the first year after cART. However, those patients whose CD4+ counts at 2 years suggest a persistent discordant immunologic response are more likely to subsequently progress clinically.
Our results are generally in agreement with those of previously conducted studies assessing the clinical significance of discordant immunologic responses after cART.4-40 In a study of 2236 patients initiating cART,8 an increased risk of disease progression or death was observed in immunologic nonresponders, such that the CD4+ cell count at month 6 was predictive of clinical events at 5 years of follow-up. This study used 4 different definitions of 6-month CD4+ count response, including (1) change from baseline of <50 cells per cubic millimeter, (2) 6-month CD4+ count as a continuous variable, (3) 6-month CD4+ count as a categorical variable <200 or ≥200 cells per cubic millimeter, and (4) various clinical groups such as complete or incomplete or absent responses based on change from baseline.8 Patients in this study differed from our cohort in that approximately 75% were treatment experienced and all initiated therapy with a protease inhibitor (PI)-based regimen. The prognostic significance of immunologic discordance in patients initiating first-line PI-based therapy was also assessed in a prospective cohort of 150 patients followed over a period of 30 months.6 The incidence of ADIs and death among patients with immunologic discordance in this study was 21%, compared with a rate of 2% for individuals with a concordant response. Similar findings were attained in recent publications by Moore et al23 and Tan et al,24 in that immunologic discordance at 3 to 9 months after the initiation of cART in antiretroviral-naive patients was associated with a relative hazard of a clinical event of 1.87 (95% CI: 1.15 to 3.04) and 4.83 (95% CI: 2.10 to 11.12), respectively. Taken all together, despite differences in study populations, durations of follow-up and subtleties in the definition of immunologic discordance and clinical outcomes or events of interest, the bulk of published data consistently demonstrates that individuals with immunologic discordance face a poorer prognosis when compared with individuals with a concordant response. Our results add to this body of literature by determining that long-term CD4+ count response at 2 years continues to be predictive of mortality. Future research efforts focusing on this group of patients should seek to identify the most appropriate course of action to prevent or reverse the immunologic discordance.
Limitations of our analysis include the retrospective nature, limited data on comorbidities, and the potential for missing data to bias results. Comorbidities were limited to hepatitis C but other comorbidities such as cardiovascular disease risk factors could be important. Incomplete ascertainment of death is a potential critical limitation but is not viewed to be biasing the results as the missing data should be consistent across the entire population (immunologically discordant and concordant). Another limitation was the lack of cause of death data, although recent studies are departing from such analyses.39 Furthermore, although it would be of interest to know if individuals with discordant responses were at increased risk of important ADIs, these clinical events were rare and there was no ADI-specific data. Although larger than our previous analyses, the number of events occurring in our cohort still limited the statistical power of the analysis.23,40 This may partly explain why discordance at 1 year was not identified as a correlate of death.
An important clinical consideration for these patients is their optimal management. There are no current guidelines on the management of immunologically discordant individuals.9,41 This clinical scenario remains challenging, particularly because few long-term natural history and therapeutic studies have been published.9,42-45 Proposed therapeutic options include interleukin (IL)-2, treatments to increase IL-7, and preferential use of PI-based regimens.9,42-45 However, given the absence of clear clinical benefit with these interventions, the ideal management of immunologic discordance is unknown.
As our results demonstrate poorer prognosis for these patients with immunologic discordance, strategies focused on limiting immune destruction and avoiding the effects of natural immune senescence with aging should be evaluated. These would include earlier cART initiation in terms of baseline CD4+ count and/or starting therapy at a younger age. Another strategy would be pursuing intervention studies aimed at improving the CD4+ count response.
We would like to thank all the participants for allowing their information to be a part of the CANOC collaboration.
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APPENDIX I: THE CANOC COLLABORATION
Community Advisory Committee: Sean Hosein (chair), Bruno Lemay, Shari Margolese, Evelyne Ssengendo, Zoran Stjepanovic.
Investigators: The CANOC Collaboration includes: Community Advisory Committee: Sean Hosein (Chair), Bruno Lemay, Shari Margolese, Evelyne Ssengendo; Investigators: Gloria Aykroyd (Ontario HIV Treatment Network), Louise Balfour (University of Ottawa, Contributes to the Ontario HIV Treatment Network), Ahmed Bayoumi (University of Toronto, Contributes to the Ontario HIV Treatment Network), Jason Brunetta (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), John Cairney (University of Toronto, Contributes to the Ontario HIV Treatment Network), Liviana Calzavara (University of Toronto, Contributes to the Ontario HIV Treatment Network), Benny Chang (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Curtis Cooper (University of Ottawa, Contributes to the Ontario HIV Treatment Network), Fred Crouzat (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), David Fletcher (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Kevin Gough (St. Michael's Hospital, University of Toronto, Contributes to the Ontario HIV Treatment Network), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Richard Harrigan (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Marianne Harris (British Columbia Centre for Excellence in HIV/AIDS), George Hatzakis (McGill University), Malcolm Hedgecock (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Robert Hogg (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), Mark Hull (British Columbia Centre for Excellence in HIV/AIDS), Don Kilby (University of Ottawa, Ontario HIV Treatment Network), Marina Klein (Montreal Chest Institute Immunodeficiency Service Cohort, McGill University), Colin Kovacs (Maple Leaf Medical Clinic, Univeristy of Toronto, Contributes to the Ontario HIV Treatment Network), Richard Lalonde (The Montreal Chest Institute Immunodeficiency Service Cohort and McGill University), Viviane Lima (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Mona Loutfy (Maple Leaf Medical Clinic, Women's College Research Institute, Women's College Hospital, University of Toronto, Contributes to the Ontario HIV Treatment Network), Nima Machouf (Clinique Medicale l'Actuel, Université de Montréal), Ed Mills (British Columbia Centre for Excellence in HIV/AIDS, University of Ottawa), Barry Merkley (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Peggy Millson (University of Toronto, Contributes to the Ontario HIV Treatment Network), Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), David Moore (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Alexis Palmer (British Columbia Centre for Excellence in HIV/AIDS), Janet Raboud (University of Toronto, University Health Network, Contributes to the Ontario HIV Treatment Network), Anita Rachlis (University of Toronto, Contributes to the Ontario HIV Treatment Network), Stanley Read (University of Toronto, Contributes to the Ontario HIV Treatment Network), Sean Rourke (Ontario HIV Treatment Network, St. Michael's Hospital Centre for Research on Inner City Health, University of Toronto), Marek Smieja (McMaster University, Contributes to the Ontario HIV Treatment Network), Irving Salit (University of Toronto, Contributes to the Ontario HIV Treatment Network), Graham Smith (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Darien Taylor (Canadian AIDS Treatment Information Exchange Contributes to the Ontario HIV Treatment Network), David Tilley (Maple Leaf Medical Clinic, Contributes to the Ontario HIV Treatment Network), Benoit Trottier (Clinique Medicale l'Actuel, Université de Montréal), Chris Tsoukas (McGill University), Sharon Walmsley (University of Toronto, Contributes to the Ontario HIV Treatment Network), and Wendy Wobeser (Queens University, Contributes to the Ontario HIV Treatment Network).
Analysts and Staff: Svetlana Draskovic (British Columbia Centre for Excellence in HIV/AIDS), Mark Fisher (Ontario HIV Treatment Network), Sandra Gardner (University of Toronto), Nada Gataric (British Columbia Centre for Excellence in HIV/AIDS), David Milan (British Columbia Centre for Excellence in HIV/AIDS), Sergio Rueda (Ontario HIV Treatment Network), Anya Shen (British Columbia Centre for Excellence in HIV/AIDS), Benita Yip (British Columbia Centre for Excellence in HIV/AIDS).