HCV-Infected Individuals at Increased Risk for Immune Thrombocytopenia Purpura and Autoimmune Hemolytic Anemia

February 26, 2009 — The incidence of 2 severe autoimmune cytopenias — immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA) — has been shown to be elevated among individuals infected with hepatitis C virus (HCV). Research published in the February 23 issue of the Archives of Internal Medicine reveals that HCV-infected patients in the Veterans Affairs (VA) health system were at increased risk of developing ITP. However, those who underwent treatment were also at increased risk for AIHA.

"Prior studies suggesting that HCV might be an etiologic risk factor for the development of autoimmune cytopenias have been based on small series of patients from single institutions," write Elizabeth W. Chiao, MD, MPH, from the Department of Medicine, Baylor College of Medicine, Houston, and the Houston Center for Quality of Care and Utilization Studies, Health Service Research and Development Service, Michael E. DeBakey Veterans Affairs Medical Center, Texas, and colleagues. "To our knowledge, no large study has been conducted. Given that US military veterans have a high prevalence of HCV infection (5%), this population provides a unique opportunity to observe HCV-related phenomena."

To determine the effect of HCV infection on the incidence rates of ITP and AIHA, researchers analyzed the inpatient and outpatient records as well as pharmacy data from HCV-infected (n = 120,691) and matched uninfected (n = 454,905) veterans. The diagnosis of ITP and AIHA was identified via hospitalization codes. Those with a prior diagnosis of lymphoproliferative disease, HIV, or cirrhosis were excluded from the analysis.

"In this large national cohort study including over half a million US veterans, we observed HCV-infected persons to be at increased risk of ITP and AIHA," explain the authors. A Cox proportional hazards regression model revealed that the hazard ratios (HRs) for ITP and AIHA were 1.8 (95% confidence interval [CI], 1.4 – 2.3) and 2.8 (95% CI, 1.8 – 4.2), respectively.

"Because both ITP and AIHA have been previously associated with interferon alfa use, we were also interested in assessing pharmacy data to account for the effects of HCV treatment," write Dr. Chiao and colleagues. While the incidence of ITP was elevated among both treated and untreated HCV-infected individuals, the incidence of AIHA was only elevated among those who had received treatment (HR, 11.6; 95% CI, 7.0 – 19.3).

These findings were further illustrated by examining the Kaplan-Meier curves of the cumulative incidence of each of the outcomes. The cumulative incidence of ITP was significantly greater among HCV-infected individuals vs matched control individuals (P < .001) and remained significant following censorship at the time of treatment (log rank test; P = .002). However, the cumulative incidence of AIHA was significantly greater among HCV-infected individuals vs matched control individuals (P < .001), but this difference was no longer significant following censorship at the time of treatment (log rank test; P = .84).

The main advantage of this study is that it is the first involving a large cohort to evaluate the effect of HCV infection on autoimmune cytopenias. However, there were several potential limitations. These included that the diagnoses of ITP and AIHA were not confirmed through a review of the medical records; that the calculation of the cumulative incidence of ITP and AIHA did not take into consideration other competing risks, which could have resulted in biased estimates; that the study involved a relatively short follow-up, which resulted in fewer ITP and AIHA events, thereby limiting the power to detect differences; that the incidence rates of ITP and AIHA in this study were higher than the incidence rates previously reported for the general population; that the HCV genotype or the rates of sustained virologic response after treatment were not confirmed via laboratory data; that there was a limited ability to account for bias introduced by other factors, which resulted in patients being excluded from treatment based on their physician's decision; and last, that the study population was made up almost entirely (96.5%) of men.

Several biological mechanisms have been suggested to explain the relationship between HCV infection and the development of ITP. The current findings illustrate that chronic HCV infection may cause ITP via a platelet-specific mechanism in addition to the occurrence of generalized autoimmunity. Thus, the researchers suggest that the term "HCV-associated thrombocytopenias" may be appropriate for future studies. Furthermore, interferon alfa has previously been associated with ITP and AIHA. The results of this study reinforce the theory that immunomodulatory effects of interferon alfa many cause an increased risk for autoimmune cytopenia.

"Future research is needed to clarify the underlying mechanisms and implications of our findings," conclude the authors.

This study was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health, and the Houston VA Health Services Research and Development Center of Excellence. The authors have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:357–363.