Due to its large size, geographically diverse treatment centers, representative proportion of black patients, and use of FDA-approved medications, the IDEAL study population represents a unique sample of patients who sought treatment for HCV infection in the U.S. Further, the criteria for HCV treatment eligibility in this postapproval study were similar to those recommended for use in routine clinical practice by expert guidelines and outlined in the product information approved by the FDA.11,8–22
In this context, the findings that nearly 25% of patients presenting to medical centers for treatment of hepatitis C were ineligible for PEG-IFN/RBV and that black Americans were 65% more likely than nonblack Americans to be ineligible for therapy have important public health implications, particularly in the context of the Institute of Medicine report on viral hepatitis and liver cancer in the U.S.23
Hepatitis C disproportionately affects black Americans; the prevalence of chronic HCV infection and resultant liver disease is higher among blacks than other racial and ethnic group in the U.S.1,24
Further, among black patients in the IDEAL study and other clinical trials, the sustained virologic response rates to treatment with PEG-IFN/RBV have been markedly lower than those for patients from other populations with similar clinical characteristics.8–10,15
Recent genome-wide association studies suggest that the observed differential response is in part due to genetic polymorphisms near the gene for IL-28B; other research suggests that the difference is unlikely to be explained by factors that may be modifiable, such as differences in drug pharmacokinetics or patient adherence.7
In this context, the observation that black Americans are less likely to be eligible for treatment with PEG-IFN/RBV indicates that the difference in successful HCV treatment outcomes between black and nonblack patients is even greater than what has been reported in clinical trials in which only treatment-eligible patients are observed, particularly if blacks are less likely to enroll in HCV treatment trials, as has been seen in clinical trials of other chronic medical conditions.25
Further, whereas the use of specific HCV protease inhibitors, such as telaprevir or boceprevir, will increase the SVR rate among HCV-infected patients, including blacks, these treatments will not impact the rate of HCV treatment eligibility in clinical trials or practice because PEG-IFN/ RBV will remain the backbone of treatment regimens involving these first-generation protease inhibitors.26,27
Unlike host genetic polymorphisms, barriers to HCV treatment eligibility may be amenable to interventions that could improve uptake of therapy. Among the reasons for HCV treatment ineligibility, inadequately controlled diabetes mellitus was more common among blacks than nonblacks. This finding is not unexpected because diabetes mellitus, higher hemoglobin A1c levels (among persons with diabetes mellitus), and medical complications associated with diabetes are more prevalent among blacks than non-Hispanic white adults in the U.S.28,29
Although the explanation for the diabetes-related racial differences among patients presenting for HCV treatment in IDEAL is likely multifactorial, diabetes represents a modifiable barrier to treatment. Previous studies have suggested that inadequate access to primary medical care and health insurance may, in part, explain the increased prevalence of suboptimal diabetes control among blacks; improved access to healthcare may therefore enhance HCV treatment eligibility among black Americans.30–32
Blacks were also more likely to be ineligible due to renal insufficiency. Although a single serum creatinine measurement is insufficient to diagnose chronic kidney disease, black Americans are more likely than non-Hispanic whites to have estimated glomerular filtration rates less than 60 mL/min/1.73 m2
or elevated urinary albumin-to-creatinine ratios, and they are at greater risk for renal disease.33,34
Although the cause of abnormal renal function was not assessed, the association between diabetes and renal disease suggests that the observed racial differences in diabetes control may also have contributed to a greater risk of renal insufficiency among blacks presenting for HCV treatment.35
In addition, compared with nonblacks, body weight was higher among treatment-eligible and -ineligible black patients; given the association between increasing body-mass index and chronic kidney disease (CKD), this difference may also have contributed to the increased prevalence of abnormal renal function among blacks.35
Because of the interplay between renal disease, diabetes mellitus, obesity, and other medical conditions (e.g., hypertension), more effective comprehensive medical care may also help address this racial difference. Of note, HCV treatment ineligibility on the basis of impaired renal function is largely due to markedly decreased clearance of RBV, leading to increased risk and severity of anemia during therapy.36
Based on this, RBV is not approved for use in persons with estimated creatinine clearance <50 mL/min; however, pharmacokinetic studies suggest that adjustment of RBV dose based on creatinine clearance may effectively achieve safe, therapeutic drug exposure.37,38
Further research is needed to determine whether ribavirin dose adjustment is an effective strategy for treating HCV in patients ineligible for treatment with ribavirin due to renal impairment.
Another factor that contributed to higher rates of HCV treatment ineligibility among black patients was neutropenia. Given that constitutional neutropenia without apparent clinical consequence is more prevalent among blacks, this observation was not unexpected.13
Recently, the VIRAHEP-C study, which evaluated response to PEG-IFN/RBV in black and white Americans, applied a less conservative absolute neutrophil count value (>l,000/mm3
) for HCV treatment eligibility; importantly, no increased frequency of neutropenia-associated morbidity was observed.10
Further, studies have failed to document a relationship between the development of interferon-related neutropenia and the incidence of bacterial infections.39,40
Accordingly, recent revisions to the HCV treatment guidelines from the American Association for the Study of Liver Disease recommend that neutropenia should not prevent treatment with PEG-IFN/RBV.11
Wider application of a less conservative ANC threshold for PEG-IFN therapy would increase HCV treatment eligibility among blacks. For example, if an ANC threshold of ≥ 1,200/ mm had been utilized in the present study, 50% of the black patients excluded because of neutropenia would have been eligible. Accordingly, practice guidelines and clinical trials of PEG-IFN-based therapy, including those with novel direct-acting antiviral drugs, should adopt a less conservative ANC threshold (e.g., 1,000 or 1,200 cells/mm3
) to minimize the medically unnecessary exclusion of black patients. Similar to neutropenia, more blacks than nonblacks were ineligible for HCV treatment due to anemia. This racial difference mirrors population-based studies which demonstrate that black Americans have lower average hemoglobin levels than whites even after controlling for the greater prevalence of conditions like thalassemia and/ or iron-deficiency.13,41
Because anemia due to PEG-IFN/ RBV may have clinically significant consequences, the application of more liberal eligibility criteria (e.g., lower required hemoglobin level) is not likely to be feasible. HCV treatment regimens that do not include RBV may be needed to overcome this barrier to therapy.
Our study has several limitations. First, the HCV treatment eligibility criteria applied in this clinical trial may be more restrictive than those used by physicians in clinical practice, which could result in a higher rate of treatment ineligibility than would be observed in other settings. However, in this study of FDA-approved medications the eligibility criteria were modeled on expert guidelines and current product labels for both PEG-IFNs. Second, whereas we did not detect differences in the screen failure rate at academic and community sites, we do not have data regarding the rate of HCV treatment, if any, of the ineligible patients at each individual site and cannot exclude the potential for differences in clinical practice at the academic and community sites. Third, we cannot exclude the possibility of selection bias if blacks with HCV and comorbid medical conditions were more likely than otherwise healthy HCV-infected blacks to seek primary medical care and then subsequently be referred for HCV treatment. If otherwise healthy blacks with HCV infection are less likely to access primary medical care than are otherwise healthy whites with HCV infection, our findings may overestimate racial differences in HCV treatment eligibility. Data on possession of health insurance might have provided a surrogate marker for access to medical care, but these data were not collected at screening. Fourth, because we sampled patients who presented to expert medical centers seeking HCV treatment, these data are highly likely to overestimate the proportion of patients eligible for HCV therapy compared with the general population in the U.S. Indeed, several reports suggest that as many as 60% of unselected HCV-infected patients may not be candidates for current HCV treatment.5,18
Thus, this analysis represents a conservative estimate of rates of ineligibility in black and nonblack Americans. Fifth, categorization of race was self-reported. Recent analysis of DNA from a large subset of patients enrolled in the IDEAL study suggests that the misclassification rate for race was ≈ 8%.7
Although not insignificant, this is unlikely to influence the overall findings. Sixth, whereas we would have liked to perform an assessment for differential rates of eligibility between Hispanic whites and non-Hispanic whites, we were unable to do so because data on this racial distinction were not collected at screening. Finally, patients were excluded based on the findings of clinical and laboratory assessments performed at only one or two time-points. In clinical practice, medical interventions (e.g., better treatment of diabetes) could effectively correct some of these exclusionary abnormalities.
In conclusion, compared with nonblacks, black Americans are ≈65% less likely to be eligible for HCV treatment. Although there are multiple factors underlying this observed racial difference, several barriers to HCV treatment that were more prevalent in blacks, such as inadequately controlled diabetes mellitus and renal insufficiency, may be overcome with comprehensive strategies to provide effective medical care, thereby increasing eligibility for current and future HCV treatments that include PEG-IFN/RBV In addition, the adoption of less conservative requirements for absolute neutrophil counts would be expected to make more blacks eligible to receive HCV treatment. Nonetheless, when considered in the context of markedly lower SVR rates for blacks treated with PEG-IFN/RBV, the finding that blacks are also significantly less likely to be eligible for this treatment underscores the need for novel antiviral regimens to impact HCV disease among black Americans.