Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation

Abstract

Background: Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART.

Methods: A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models.

Results: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation.

Conclusions: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening.

Keywords: CRP; HIV; anemia; antiretroviral therapy; inflammation.

Figure 1.

Case-cohort study. A random subcohort of 270 individuals and any additional cases from the original full cohort (AIDS Clinical Trials Group [ACTG] Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]) were part of the full case cohort. For the clinical failure case cohort, the outcome was clinical failure, which was defined as incident World Health Organization stage 3 or 4 events or death within 96 weeks after antiretroviral therapy (ART) (n = 234 controls and n = 236 cases). For the virologic failure case cohort, the outcome was virologic failure, which was defined as 2 successive plasma human immunodeficiency virus type 1 RNA levels >1000 copies/mL at or after 16 weeks post-ART (n = 246 controls and n = 165 cases). For the tuberculosis case cohort, the outcome was incident tuberculosis by 96 weeks post-ART initiation (n = 255 controls and n = 76 cases).

Figure 2.

Independent factors associated with pre–antiretroviral therapy anemia in the subcohort. Forest plot showing the odds ratio (OR) of anemia by covariates using data from the subcohort. Univariable (gray line) and multivariable (black line) logistic regression were used to calculate the OR of being anemic. Multivariable models were adjusted for sex (reference: male), country (reference: Brazil), body mass index (BMI) (reference: normal defined as 18–25 kg/m²), prior tuberculosis (reference: no prior tuberculosis), CD4 count (reference: >200 cells/µL), log viral load (reference: <4 copies/mL), albumin (reference: ≥3.5 g/dL), and C-reactive protein (reference: >10 mg/L). Country, log viral load, BMI, prior tuberculosis, and C-reactive protein were not associated with anemia in multivariable models and are not shown in this figure.

Figure 3.

Association of baseline anemia with clinical treatment failure using full case cohort. A, Using the full case cohort (n = 470), hazard ratios of clinical treatment failure by baseline anemia and baseline concurrent anemia and inflammation were calculated using univariable and multivariable Cox proportional hazards regression models. In multivariable model 1, the variables adjusted for were sex, age, body mass index (BMI), CD4 count, viral load, and C-reactive protein (CRP), and the reference group was people with no anemia. In multivariable model 2, categories were based on combination of anemia and CRP. Hazard ratio of clinical failure in nonanemic people with high inflammation (CRP ≥10 mg/L) (labeled No anemia and High CRP), anemic people with low inflammation (CRP <10 mg/L) (labeled Anemia and Low CRP), and anemic people with high inflammation (concurrent anemia and inflammation) were compared to the reference group of nonanemic people with low inflammation. Multivariable model 2 adjusted for sex, age, BMI, CD4 count, and viral load. Variables were categorized using the same definitions in Table 1. B, Kaplan–Meier curve is shown by the 4 categories. Abbreviation: ART, antiretroviral therapy.