Estimating the Number of Patients Infected With Chronic HCV in the United States Who Meet Highest or High-Priority Treatment Criteria

Abstract

We estimated the number of people infected with HCV in the United States who would qualify for immediate treatment according to the 2014 guidance.

We based fibrosis stage on biopsy results, when available, or on FIB-4 scores. We used laboratory tests and International Classification of Diseases, Ninth Revision, Clinical Modification codes to determine if patients had any qualifying comorbidities.

Of the 2.7 million people with HCV infection, we assumed that 1.35 million (50%) had been diagnosed. We estimated 457 000 met the highest and 356 000 the high-priority criteria for treatment, indicating that as many as 813 000 people could be treated immediately with new therapies. These estimates can inform planning efforts to address clinical capacity constraints and treatment costs.

New antiviral treatments for HCV can cure HCV infection quickly and with few side effects.^1,2 The new American Association for the Study of Liver Diseases–Infectious Diseases Society of America treatment guidance published in August 2014³ formalized criteria for prioritizing care among patients seeking treatments for HCV infection: liver transplant recipients and patients with advanced fibrosis (METAVIR F3) or compensated cirrhosis (METAVIR F4) and those with kidney damage should be given the highest priority for treatment, and patients with moderate fibrosis (METAVIR F2) or those with specific coinfection or comorbid conditions should be given high priority for treatment.³

High treatment costs and lack of access to a treating clinician are among the potential barriers to the uptake of HCV treatment. In response to the anticipated high cost of treating a large group of individuals with HCV infection, the National Association of Medicaid Directors issued a letter to congressional committee members soliciting policy changes to accommodate rising costs associated with breakthrough pharmaceuticals,⁴ and Medicaid programs in 35 states require prior authorization for treatment with sofosbuvir (Sovaldi).⁵ An estimate of the number of individuals who would be categorized as meeting the highest and high-priority criteria for treatment is of great interest to payers and public health officials who have to make decisions regarding eligibility for treatment and budgetary allocations for treatment and other health care services.

We estimated the number of HCV-infected patients in the United States who have already been diagnosed and are likely to have met highest or high-priority treatment criteria according to the newly published treatment guidance.³ We developed an approach that payers and other organizations can use to make ballpark estimates at the state, local, or other level about the number of patients with HCV and treatment costs.

METHODS

We used data from the 2003 to 2010 National Health and Nutrition Examination Survey (NHANES)—the most recent data available—to determine a national estimate of the number of people with chronic HCV infection in the United States.⁶ The NHANES is a nationally representative survey of the US civilian noninstitutionalized population conducted by the National Center for Health Statistics to assess the health and nutrition status of the US population. About 5000 noninstitutionalized civilians living in the 50 states and the District of Columbia are sampled each year. The NHANES includes interviews and a physical examination component. Information on demographics and other characteristics is collected through in-home interviews, and biological specimens are taken for laboratory analyses as part of the physical examination, which is conducted in a specially designed mobile examination center. Since 1999, this cross-sectional survey has been conducted continuously, with data releases every 2 years. Because of the low prevalence of HCV infection, we combined data from 4 cycles of the NHANES to produce reliable estimates.⁶

For our analysis, we used these 4 cycles of NHANES to estimate the number of HCV-infected people (those with either diagnosed or undiagnosed HCV infection) according to stage of liver disease and comorbid conditions.³ In the NHANES, having chronic HCV infection is defined as being HCV RNA positive. The blood tests necessary for the calculation of FIB-4 score were performed as part of the NHANES, along with urinary test results and selected self-reported comorbid conditions. We used SAS-Callable SUDAAN software (release 11.0; RTI International, Research Triangle Park, NC) for analyses because of the complex survey design used in NHANES, and we incorporated the survey examination weights to make our estimates representative of the noninstitutionalized civilian US population. We adjusted the examination weights to account for missing HCV testing results for some participants and multiple NHANES cycles.⁶

On the basis of the 2003 to 2010 NHANES data, we estimated the number of people with chronic HCV infection in the United States to be 2.7 million. Because of the low awareness about and asymptomatic nature of HCV infection, many people who may otherwise qualify for therapy have not been tested and identified.^7–9 We assumed that about 50% of HCV-infected people remain undiagnosed.^7–9

People With Diagnosed HCV Infection

We used data from the Chronic Hepatitis Cohort Study (CHeCS), an observational cohort of HCV-infected patients, which has been described in previous publications,^9–12 to estimate the percentages of patients with diagnosed HCV infection meeting highest or high priority for treatment. Briefly, this cohort was drawn from among more than 2.7 million patients aged 18 years or older who had a clinical service visit (i.e., outpatient or inpatient, emergency department, or laboratory test) between January 1, 2006, and December 31, 2012, at 1 of 4 sites: Geisinger Health System, Danville, Pennsylvania; Henry Ford Health System, Detroit, Michigan; Kaiser Permanente-Northwest, Portland, Oregon; and Kaiser Permanente-Honolulu, Hawaii.

In CHeCS, patients were initially identified principally on the basis of laboratory criteria and secondarily on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) criteria.^10,13 Electronic health record data and administrative data were collected for each patient and supplemented with individual chart review by trained data abstractors, who also verified chronic HCV infection. Data collected included patient demographics, medical encounters, treatment data, and laboratory, radiology, and biopsy results. Because the purpose of this analysis was to describe characteristics of patients who are still infected with HCV and potentially eligible for therapy, we assessed liver disease and comorbidities on the basis of the latest clinical data for each cohort patient through December 31, 2012 (the most recent data available).

In estimating the percentages of patients with diagnosed HCV infection meeting highest and high priority for treatment, we excluded from our analysis CHeCs patients who had died, had achieved sustained virologic response, or had received a liver transplant. Although liver transplant recipients qualify for the highest priority for treatment under current guidance, the national number of liver transplant patients alive with HCV infection is relatively small. In 2012, approximately 65 000 individuals in the United States were living with transplanted livers, of whom, from 2008 to 2012, only 30% exhibited serologic evidence of HCV infection.¹⁴

Fibrosis Staging

Liver fibrosis has traditionally been staged by biopsy; however, biopsy data are not collected by the NHANES. For NHANES participants and CHeCS patients who had not received a recent biopsy (limited to biopsy in 2004 or later), we approximated fibrosis stage by using the most current FIB-4 score. FIB-4 score has been found to increase with successive fibrosis levels and can be useful in monitoring patients who may need therapy or additional histologic evaluations.^12,15 We calculated FIB-4 score with the following formula:¹²

where AST = aspartate aminotransferase and ALT = alanine aminotransferase.

An FIB-4 score threshold of 2.5 or more was assumed to indicate a fibrosis level of METAVIR F3 or higher. We chose this threshold value on the basis of the upper limit of the 95% confidence interval (CI) for the mean FIB-4 score in approximately 400 HCV-infected patients who were staged at METAVIR F3 using biopsies (mean FIB-4 score = 2.32, 95% CI = 2.17, 2.47).¹² Because the distribution of FIB-4 scores in HCV patients is skewed, we used the upper limit of the mean, which was rounded to 2.5. Similarly, a threshold of 1.6 was assumed to indicate a fibrosis level of METAVIR F2 or higher.¹² For this analysis, because the METAVIR fibrosis scale categorizes HCV-infected people into mutually exclusive groups of METAVIR F2 or METAVIR F3, but not both, we assumed that only people whose FIB-4 score was 1.6 or higher but less than 2.5 were at the METAVIR F2 stage.

In a comparison scenario, we also included estimates when the METAVIR F3 threshold was changed from an FIB-4 score of 2.5 or more to 3.25 or more.¹⁵ Using the threshold value of 3.25 has a higher specificity for advanced fibrosis or cirrhosis but is not sensitive enough to rule out all people below this threshold who have substantial fibrosis³; thus, using this higher cutoff yielded a conservative estimate (or underestimate) of people with moderate or worse fibrosis meeting the highest priority criteria. We calculated the FIB-4 score for patients in CHeCS from routine laboratory data available in patients’ medical records; the clinician did not necessarily order the tests to obtain an FIB-4 score to assess a patient’s need for treatment.

Comorbid Conditions

We identified HCV-infected individuals who met the highest or high-priority criteria for treatment on the basis of kidney damage or other relevant comorbid conditions,³ using laboratory tests or ICD-9-CM codes (Appendix A, available as a supplement to the online version of this article at http://www.ajph.org). Because of the absence of reliable data, we could not assess all conditions meeting the treatment criteria.

To simplify presentation, we rounded all estimates to the nearest thousand.

RESULTS

Of an estimated 2.7 million people (95% CI = 2.2, 3.2) infected with chronic HCV in the United States, most (79%) were aged between 40 and 59 years at the time of the NHANES survey.⁶ A majority of HCV-infected people were male (64%) and non-Hispanic White (61%).⁶ On the basis of FIB-4 scores among HCV-infected NHANES participants, we estimated that 351 000 people (95% CI = 216 000, 540 000), or 13% (95% CI = 8%, 20%), had an FIB-4 score of 3.25 or higher, predictive of advanced fibrosis (METAVIR F3 or higher). Using the more inclusive threshold of 2.5 (instead of 3.25), we estimated that the number of people with advanced fibrosis of METAVIR F3 or higher was 513 000 (95% CI = 378 000, 675 000), or 19% (95% CI = 14%, 25%; Table 1). After adding 18 900 people (95% CI = 5400, 54 000) who had an FIB-4 score of less than 2.5 but who might qualify because of a urinary test indicating proteinuria (Appendix A), the national estimate for people meeting the highest criteria for treatment was 532 000 (95% CI = 392 000, 702 000; Table 1).

TABLE 1—

People Infected With HCV Who Met the Highest or High-Priority Treatment Criteria in the United States: National Health and Nutrition Examination Survey 2003–2010

Hierarchy of Care	Meeting Criteria, % (95% CI)	National Estimates Meeting Criteria, No. (95% CI)	Subtotal, No. (95% CI)
Highest priority			532 000 (392 000, 702 000)
METAVIR ≥ F3	19 (14, 25)	513 000 (378 000, 675 000)
METAVIR < F3 with kidney diseasea	0.7 (0.2, 2.4)	18 900 (5 400, 54 000)
High priority			513 000 (386 000, 699 000)
METAVIR F2	15 (11, 21)	405 000 (297 000, 567 000)
METAVIR < F2 with comorbiditya	4 (2, 8)	108 000 (54 000, 216 000)

Note. CI = confidence interval; infected = tested positive for HCV RNA.

^aSee Appendix A, available as a supplement to the online version of this article at http://www.ajph.org.

After excluding those meeting the highest criteria for treatment, we estimated that 405 000 people (95% CI = 297 000, 567 000) had an FIB-4 score of 1.6 or more (but < 2.5), predictive of METAVIR F2 (Table 1). After adding in people with comorbid conditions such as HIV coinfection (Appendix A), the national estimate for people meeting the high-priority criteria for treatment was 513 000 (95% CI = 386 000, 699 000). In total, we estimated that about 1.0 million people (532 000 + 513 000; 95% CI = 875 000, 1 245 000) met highest or high-priority criteria in the United States; the majority (81%; 95% CI = 73%, 87%) of these people were born between 1945 and 1965.

If one assumes that 50% of the 2.7 million HCV-infected people have been tested and confirmed positive^6–9—that is, known to be HCV infected—then 1.35 million people are living with a diagnosed chronic HCV infection. We estimated the distribution of fibrotic stage and comorbid conditions among people whose HCV infection had been diagnosed from CHeCS data. From among the 14 708 CHeCS patients with confirmed HCV infection, we excluded 3922 who had died, achieved sustained virologic response, or received a liver transplant while under observation. Of the remaining 10 786 patients, we excluded 6% because they had no biopsy and no laboratory tests for FIB-4 calculation, which suggested that they had received little workup or had been lost to follow-up. Of the remaining 94%, 22% had at least 1 liver biopsy in 2004 or later, and 72% had at least 1 FIB-4 measurement without biopsy. When we applied these percentages to the national estimate of HCV-infected people, the result was 297 000 people (22% of 1.35 million) with at least 1 liver biopsy and 972 000 people (72% of 1.35 million) with at least 1 FIB-4 measurement without biopsy (Figure 1).

FIGURE 1—

Cascade diagram of the estimated number of people infected with HCV in the United States according to diagnosis status and hierarchy of care: 2003–2010 National Health and Nutrition Examination Survey; Chronic Hepatitis Cohort Study, January 1, 2006–December 31, 2012.

Note. AASLD/IDSA = American Association for the Study of Liver Diseases–Infectious Diseases Society of America; ALT = alanine aminotransferase; AST = aspartate aminotransferase. FIB-4 score = [age × AST (IU/L)]/[platelet (10⁹/L) × ALT ½ (IU/L)]. FIB-4 score is calculated from routine liver function tests (ALT and AST) and platelet count test; the number of patients for whom an FIB-4 score was ordered for the purpose of treating HCV infection is unknown. An FIB-4 score ≥ 2.5 is predictive of advanced fibrosis (METAVIR F3 or higher), and an FIB-4 score ≥ 1.6 but < 2.5 is predictive of advanced fibrosis (METAVIR F2). American Association for the Study of Liver Diseases–Infectious Diseases Society of America highest or high-priority treatment criteria are based on When and in Whom to Initiate HCV Therapy.³ Chronic conditions are coinfections or comorbidities including HIV, hepatitis B virus, diabetes, and coexistent liver condition (e.g., nonalcoholic steatohepatitis) in HCV-diagnosed patients only (see Appendix A, available as a supplement to the online version of this article at http://www.ajph.org).

^aSee Denniston et al.⁶

^bSee Spradling et al.⁷ and Denniston et al.⁸

^cSee Holmberg et al.¹²

Demographic characteristics of CHeCS patients mirrored those among HCV-infected participants in NHANES. The mean age at the end of 2012 for CHeCS patients was 54.4 years, 58% were male, and 62% were non-Hispanic White. However, CHeCS patients were more likely to have advanced liver disease than HCV-infected NHANES participants. After matching by birth year, the percentages of people with an FIB-4 score of 3.25 or higher were 20% among CHeCS patients and 7% higher than the 13% estimated among HCV-infected NHANES participants.

We based stage of liver disease among CHeCS patients (whose HCV infection had been diagnosed) on biopsy results when available (as early as 2004) and on FIB-4 scores when biopsy results were not available. From the results of the most recent biopsies, we estimated that 27% of CHeCS patients were at METAVIR F3 or F4. When we supplemented the most recent biopsy results with the most recent measurement of FIB-4 score, using 2.5 or higher as the threshold, we estimated that 33% of CHeCS patients were at METAVIR F3 or F4. Applying this value to the national estimate of HCV patients (Figure 1) results in an estimated 419 000 people nationwide (33% of 1.27 million) meeting the high-priority criteria for treatment. Among CHeCS patients, 3% were identified as having a fibrosis level less than METAVIR F3 but as perhaps qualifying as highest priority because of evidence of kidney disease (Appendix A). The total estimated number of people categorized as meeting the criteria for highest treatment priority was 457 000 nationwide (36%; Figure 1).

Among the remaining CHeCS patients who did not meet the highest priority treatment criteria but who might potentially have met the high-priority treatment criteria, 28% had evidence of moderate fibrosis (METAVIR F2 by biopsy or FIB-4 ≥ 1.6 and < 2.5) or had a qualifying coinfection or comorbidity, corresponding to 356 000 (28% of 1.27 million) people nationwide. In total, the national estimate of people meeting highest or high-priority criteria was 813 000, or about 64% of those living with a diagnosed chronic HCV infection (Figure 1).

DISCUSSION

We estimate that about 1 million noninstitutionalized people with HCV infection in the United States met the highest or high-priority criteria for treatment. Of these, we estimate that 813 000 people had been diagnosed and were in care. By estimating the number of HCV-infected people who have been diagnosed and met treatment criteria, we hope to inform planning and other efforts to address barriers to HCV treatment, including enhanced clinical capacity and budgetary projections.

Our results may constitute overestimates of the highest or high-priority treatment populations who will be treated in the short term because the staging of liver disease in this analysis was mostly based on FIB-4 score, and only a relatively few patients (22% of CHeCS patients) had been biopsied. The laboratory tests that allowed us to obtain an FIB-4 score were not necessarily ordered to assess a patient’s need for treatment. Therefore, the number of patients for whom the tests were ordered for the purpose of treating HCV infection is presumably low. Thus, these estimates likely represent the maximum number of people currently in care who should get immediate therapy because clinicians may not be aware that their patients are at a stage of liver disease that qualifies them for prioritization. Even for those known to have a more advanced stage of liver disease, life-limiting conditions, deaths, and patient or physician choice may limit the number of those patients receiving new antiviral therapies.

Chronic HCV infection is not widely acknowledged as an urgent public health issue despite increasing health system burden^16,17 and mortality.^18–20 In the United States, decedents with HCV infection listed among the causes of death on their death certificates were more than 20 years younger than decedents without HCV infection.²⁰ Thus, the need to treat those at most risk of immediate mortality and morbidity is urgent.

The findings of this study are subject to several limitations. Our estimates are limited to the civilian noninstitutionalized population. The NHANES does not include homeless individuals, active military members, or people residing outside of households, such as in nursing homes or in prisons. The use of data from NHANES 2003 to 2010 may have resulted in a slight underestimation of the number of patients with advanced fibrosis due to disease progression in more recent years. Also, the number of people qualifying for treatment was mostly based on FIB-4 values. The purpose of using the FIB-4 score in this analysis was to estimate how many patients qualified as highest or high priority for treatment at the national level, and we chose the FIB-4 score thresholds of 2.5 and 1.6 on the basis of the upper limits of mean FIB-4 scores¹² to balance the chances of underestimation and overestimation. These thresholds may be different from the cutoffs that maximize sensitivity and specificity at the patient level and have not been evaluated for their positive predictive value and negative predictive value at the individual level. Incidentally, in a recent analysis,²¹ FIB-4 scores of 2.5 or more were associated with increased incidence of hepatocellular carcinoma, which is among the most severe complications of chronic, untreated HCV infection. Despite the fact that CHeCS cohort is large and geographically and clinically diverse, the CHeCS patients’ distribution by fibrosis stage may not be generalizable to all people who have been diagnosed with chronic HCV infection. Finally, we did not include some comorbid conditions, such as debilitating fatigue, because of the absence of data (Appendix A). However, generally speaking, the prevalence of comorbid conditions in people with mild liver disease (< METAVIR F2) is expected to be low.

Potential demand for HCV treatment may require rapid and substantial increases in clinical capacity. However, although widespread initiation of HCV therapies may be associated with substantial and perhaps prohibitive costs, estimating the number of people actually ready for therapy—as we have done—may provide useful information as to the affordability of particular treatment policies and priorities. Increasing morbidity and mortality rates and the associated health system costs and burdens that result from chronic HCV infection can potentially be reduced if barriers to uptake of therapy for HCV infection are addressed.