In the largest study of the subject to date, researchers have found that HIV-positive individuals with a history of injection drug use, CD4 cell counts below 200 cells/mm3, or elevated ALT liver enzyme levels are at greater risk of falsely negative antibody tests for HCV infection. The findings were reported in the online edition of the journal Clinical Infectious Diseases.
Chronic seronegative hepatitis C virus (HCV) infection occurs when HCV antibody tests report false negative results despite the presence of HCV as confirmed by RNA tests. Seronegative HCV infection is estimated to occur in one in 250,000 blood donors (0.0004%). This is mostly due to acute HCV infection (i.e., early infection before the immune system has developed antibodies), but can also occur in chronic HCV infection. HIV-positive people are at greater risk of chronic seronegative HCV infection, with reported prevalence ranging from 0% to 13.2% depending on the test assays used and population studied. Risk factors have been difficult to identify because of the small number of cases.
In this study, researchers from the United States combined data from four American cohorts of HIV-positive individuals, including the large, multicentre (16 site) FRAM (Fat Redistribution and Metabolic Change in HIV infection) study cohort. The cohorts contributed HIV-positive participants towards analysis as follows:
- 1,151 from FRAM, which collected data between 2000 and 2002.
- 345 from the University of Southern California, Los Angeles HIV & Hepatitis clinic, between 1993 and 1999.
- 130 from the Iowa City HIV clinic, 1988 to 2000.
- 229 from the San Francisco Research and Access to Care for the Homeless (REACH) cohort, 1996 to 2000.
HCV antibody testing was done using the HCV EIA 2.0 (Abbott) assay, the standard tool at most large laboratories; chronic HCV infection was confirmed by HCV RNA (Bayer Versant 3.0 bDNA assay).
Of the total 1,855 HIV-positive participants, 1,174 were HCV antibody negative by EIA test. The FRAM cohort is considered “representative of HIV-infected patients in medical care in the United States”. Overall, the demographics of the 1,174 HCV antibody negative participants were inclusive of a range of characteristics (10% to 26% female, 26% to 84% white race, median CD4 cell count 86 to 380 cells/mm3, median age 37 to 41).
HCV prevalence and risk factors
Among HCV antibody-negative individuals in the four cohorts, percentages of seronegative HCV infection (positive tests for HCV RNA) ranged from 1% to 5%; the figure was 37 (3%) overall, with a 95% confidence interval (CI) of 2% to 4%.
Among the 93 total HCV antibody-negative IDUs (from all cohorts), the prevalence of seronegative HCV was 15% (95% CI, 8.5% to 24%).
Analysis identified the following as risk factors for seronegative HCV infection:
- History of injection drug use (IDU): odds ratio (OR) = 5.8 (95% CI, 2.7-12.8), p <.0001
- Current CD4 cell count < 200 cells/mm3: OR=2.3 (95% CI, 1.1-4.8), p=.025
- Increasing alanine aminotransferase (ALT) level: OR=2.0 for each doubling in level (95% CI, 1.3-3.2), p =.002
Sex, ethnicity, age, and HIV viral load (RNA level) were not identified as risk factors.
For the subgroup of IDUs who either had a CD4 cell count < 200 cells/mm3 or an ALT greater than the upper limit of normal, seronegative HCV prevalence was 24% (95% CI, 13% to 39%).
Regarding the current antibody test assays used, the researchers concluded that, although a more sensitive HCV 3.0 EIA is available, “the HCV EIA 2.0 assay is … sufficiently sensitive … to determine [HCV] antibody status.” Regarding the failure of the antibody test to identify all cases of hepatitis C infection in HIV-positive patients, “HCV RNA testing should be performed in anti-HCV-negative, HIV-infected patients, especially those with a history of IDU and either a CD4 cell count < 200 cells/ul or an abnormal ALT level.”
Reference:
Chamie G et al. Factors associated with seronegative chronic hepatitis C virus infection in HIV infection. Clin Infect Dis 44 (online edition), 2007.