These findings indicate that hepatitis B, HIV disease, hemochromatosis, and alcohol use are strongly associated with hepatitis C and may be important in contributing to increased mortality in hepatitis C-infected individuals, consistent with previous research on the influence of these diseases on the clinical course of hepatitis C. Hepatitis B, HIV disease, and alcohol use were common among hepatitis C deaths, indicating that interventions targeting these conditions may be an efficient means for attempting to limit death and severe disease from hepatitis C. This analysis further demonstrates a synergistic influence of multiple exposures on hepatitis C being listed as a COD.
Hepatitis B was the condition most strongly associated with hepatitis C, consistent with previous studies on hepatitis B exacerbating hepatitis C-related liver disease. These studies have shown that the two viruses act synergistically in the development of chronic liver disease.20–22
The strong association between these two conditions is consistent with the synergistic effects described in these other studies. However, given the high likelihood of residual confounding due to poor measurement of injection drug use, as well as confounding due to unmeasured common risk factors for both infections (such as blood transfusions), much of this association is probably driven by shared modes of transmission. Detection bias may also have influenced these results, with hepatitis C deaths more likely to be screened for other viral hepatitis infections than control deaths. Nevertheless, an association of this magnitude is unlikely to be accounted for by bias and uncontrolled confounding alone.
The association of hepatitis B with hepatitis C differed according to alcohol use and HIV disease. Although alcohol use, HIV disease, and hepatitis B have each been identified as potentially exacerbating the progression of hepatitis C disease,6,9–12,20–22
the extent to which these factors interact with one another has not been well studied. The results of this analysis suggest that co-occurrence of hepatitis B and alcohol use or hepatitis B and HIV disease may act synergistically in advancing the progression of hepatitis C disease. This should be interpreted cautiously because of possible detection bias, in which people with HIV disease and hepatitis B or those with hepatitis B and alcohol use are more likely to be screened for hepatitis C than people with only one of those conditions present.
HIV disease was strongly associated with hepatitis C and occurred in more than 10% of hepatitis C deaths, making it an important contributor to the population burden of advanced hepatitis C disease. These results are consistent with the large body of literature showing that HIV infection hastens progression of chronic liver disease among hepatitis C-infected people.9–12,28
Potential mechanisms for this observation include the hepatotoxic properties of highly active antiretroviral therapy (HAART), the tendency of HAART drugs to cause an increase in hepatitis C viral load, and a reduction in hepatitis C antibodies due to HIV-induced impairment of B-cell function.11,29
Despite the relatively well-described role of HIV in hepatitis C-related disease, some of the observed effect is certainly due to residual confounding from shared modes of transmission as well as detection bias in which people with hepatitis C are more likely to be screened for HIV. Nevertheless, given both the strong association of HIV disease with hepatitis C and its common occurrence among hepatitis C deaths, people co-infected with these viruses as well as with HIV alone may warrant targeted intervention to mitigate the effects of chronic hepatitis C or prevent hepatitis C infection from occurring.
Alcohol use was strongly associated with hepatitis C mortality and was reported in nearly one-fifth of all hepatitis C deaths, a proportion that is likely an underestimate.30
Previous research has shown alcohol use to be a strong risk factor for development of severe liver disease among hepatitis C-infected individuals.6,31,32
The results of this analysis are consistent with that body of research, although some of the observed association is likely due to residual confounding from injection drug use. Hepatitis C deaths also may be more likely to have their alcohol use status ascertained and subsequently recorded on the death certificate. Given both the strength of the association between alcohol use and severe hepatitis C disease6,13,33
as well as the high occurrence of alcohol use among hepatitis C deaths, mitigation of this exposure will be critical in reducing the burden of hepatitis C-related liver disease on a population level.
Although relatively strongly associated with hepatitis C, hemochromatosis occurred infrequently among hepatitis C deaths. Prior studies have shown that elevated levels of iron in the liver may promote persistence of chronic viral hepatitis infections, development of more severe liver disease in hepatitis C-infected people, and less successful interferon treatment.15,16,34
Hemochromatosis also may be a risk factor for acquiring hepatitis C, as therapeutic phlebotomy and injected chelation therapy may increase parenteral exposure. However, people with hepatitis C were probably more likely than those in the control groups to be screened for high iron levels, which would have resulted in positive bias of ORs. As hemochromatosis occurred infrequently among hepatitis C deaths, clinical interventions to lower iron levels among individuals with hepatitis C would likely only mitigate a small proportion of hepatitis C-related disease and mortality, but may be useful in individual clinical situations.
The association of hemochromatosis with hepatitis C appeared to be modulated by alcohol use, although results were somewhat inconsistent across control groups, likely due to the extremely low frequency of hemochromatosis among hepatitis C cases. While both high iron levels and alcohol use separately have been implicated in exacerbating hepatitis C disease,6,16
little research has explored the existence of a synergistic effect of these exposures.
The moderate association between hepatitis C and TB may be explained by residual confounding due to HIV disease, but several of the first-line drugs for TB treatment, including isoniazid and rifampin, are known to have hepatotoxic effects.17,18
It is possible that administration of such drugs, especially given the long duration of TB treatment, may hasten the progression of hepatitis C-related liver disease. The association between TB and hepatitis C must be interpreted cautiously, however, as TB was extremely rare among hepatitis C deaths. The low frequency of this exposure would also make any intervention to assess hepatitis C status before initiation of directly observed therapy an inefficient means to reduce the burden of hepatitis C-related liver disease.
Our findings must be interpreted with caution for several reasons. Limitations of using death certificate data can include varying quality and type of information collected across states, differences in how physicians complete death certificates, and lack of information on other important risk factors for hepatitis C, such as treatment and duration of infection.
In addition, despite the careful selection of three control groups, selection bias was impossible to avoid entirely. Results were qualitatively consistent across the three control groups, however, with nearly all observed associations being in the same direction and of similar magnitude. Circulatory disease controls tended to result in ORs of greater magnitude (more positive), while digestive disease controls tended to have ORs of lesser magnitude (less positive). This may be due to the fact that circulatory diseases were actually negatively associated with many of the exposure conditions. While only non-liver-related digestive conditions were used to select the digestive disease controls, this group was probably more similar to hepatitis C case deaths than the other two control groups with respect to certain factors. The number of CODs recorded for digestive disease controls was similar to that of the hepatitis C cases, indicating that these two groups may tend to either experience similar rigor in medical screening or truly have more conditions present at the time of death. Unfortunately, the largely consistent results across control groups could be an indicator of appropriate control group selection or a common bias operating across all control groups.26
Another bias, analogous to Berksonian bias,35
may have affected our results. If hepatitis C and the exposure under study both influence the probability of death, then conducting a study using only deaths amounts to stratification on what is termed a “collider variable,” which would induce an association between hepatitis C and the exposure under study.36
It is likely that there was substantial measurement error in classification of both hepatitis C status and the comorbid conditions assessed. A number of published studies have indicated that death certificate data only capture a modest proportion of all hepatitis C deaths.37,38
Furthermore, the hepatitis C case definition employed may have been nonspecific, as deaths were included that listed hepatitis C as either an underlying or contributing COD. Results of this analysis were similar, however, when cases were limited to only those listing hepatitis C as an underlying cause. The degree of misclassification of hepatitis C as a COD may also vary according to exposure status, with some deaths, such as those listing hepatitis B, much more likely to have their hepatitis C status ascertained. Likewise, exposures such as HIV disease, alcohol use, or hemochromatosis may be more likely to be ascertained for hepatitis C deaths than for other deaths. Simultaneous differential misclassification of exposure and disease can lead to bias toward or away from the null.39
Ambiguity over the temporal order of exposure and outcome was also an issue. It is difficult to accurately determine the temporal occurrence of CODs on death certificates, even under circumstances in which a physical copy of the death certificate can be examined. As such, there is no way of knowing whether the comorbid conditions actually preceded the occurrence of hepatitis C-related disease.40
Given the long, latent nature of chronic hepatitis C infection, however, it is likely that the vast majority of exposures examined were, at a minimum, concurrent with hepatitis C infection.