| |
|
Estimating [increased] Prevalence of Hepatitis C Virus Infection in the United States, 2013-2016
|
| |
| |
Hepatology March 2019
Download the PDF here
Megan G. Hofmeister,1,2 Elizabeth M. Rosenthal,3 Laurie K. Barker,1 Eli S. Rosenberg,3 Meredith A. Barranco,3 Eric W. Hall,4
Brian R. Edlin,5 Jonathan Mermin,5 John W. Ward,1,6 and A. Blythe Ryerson1
From the 1Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA; 2Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, GA; 3Department of Epidemiology and Biostatistics, University at Albany School of Public Health, State University of New York, Rensselaer, NY; 4Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA; 5National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA; 6Program for Viral Hepatitis Elimination, The Task Force for Global Health, Decatur, GA
Our analysis of NHANES data indicates an HCV antibody prevalence of 1.5% (3.7 million persons) during 2013-2016, higher than the previous NHANES estimate of 1.3% (3.6 million persons) during 2003-2010 that was produced using data collected before the 2013 revision of the NHANES HCV protocol.11 While it is possible that some of this increase is due to the change in the NHANES laboratory protocol, it also likely reflects the changing epidemic of HCV infection in the United States.1, 37, 38 From 2006 through 2012, state surveillance data from central Appalachia (Kentucky, Tennessee, Virginia, and West Virginia) demonstrated a 364% increase in the number of acute HCV infections among persons ≤30 years old.38 Furthermore, from 2011-2014, commercial laboratory data indicated a 22% increase in national rates of HCV detection among women of childbearing age.39 Overall, the number of incident hepatitis C cases reported in the United States through the National Notifiable Diseases Surveillance System increased 38.8% from 2013 through 2016, most markedly among those 20-39 years old, although increases occurred among adults of all ages.1
Continued efforts to reduce the burden of HCV infection will require improved interventions to prevent infections, expanded testing to find undiagnosed persons, and strategies to ensure treatment so that HCV-infected persons are promptly cured.
While current therapies are highly efficacious, many populations have limited access to HCV testing, care, and treatment services. A recent systematic review of the literature indicated that only half of those infected with chronic HCV were diagnosed and aware of their infection, with only a proportion linked to care (43%), prescribed HCV treatment (16%), and achieving cure (9%).40 In the Chronic Hepatitis Cohort Study, only 5.7% of patients with HCV infection potentially eligible for treatment initiated a DAA regimen prescribed in 2014.41 Kanwal et al. reported slightly higher treatment rates at the Veterans Administration, where 10.2% of the nearly 150,000 patients with chronic HCV infection seen during the first 16 months of the DAA era received treatment.42
Encouragingly, oral DAA therapy uptake has increased since the medications were first licensed. At the Veterans Administration specifically, 62,290 veterans completed oral DAA treatment between January 1, 2014, and September 30, 2016; and the Veterans Administration estimates that an additional 59,200 veterans will be cured from 2017 through 2018.43, 44 These data suggest that successful treatment, while contributing to the decline in current HCV infections, does not entirely account for the decrease observed in NHANES-estimated current HCV infection. Unfortunately, continued mortality contributes to the changes in HCV prevalence. During 2016 in the United States, 18,153 hepatitis C-related deaths were reported to the National Vital Statistics System, representing a 6.3% decrease from 2013.1 A recent analysis demonstrated that HCV is substantially underreported on death certificates (even when the main cause of death is liver-related), suggesting that the approximately 20,000 death certificates that included documentation of HCV annually during the study period underestimate mortality in chronically HCV-infected persons.45 Additionally, as the population (adults born during 1945-1965, in particular) ages, deaths from competing, non-HCV-related causes contribute to a decrease in the overall prevalence of HCV infections.
We estimated that during 2013-2016 a total of 344,100 incarcerated persons, 23,700 unsheltered homeless persons, 13,500 active-duty military personnel, and 18,900 nursing home residents were HCV antibody-positive, while 227,400 incarcerated persons, 17,400 unsheltered homeless persons, 6,900 active-duty military personnel, and 6,900 nursing home residents were living with current HCV infection.
The additional populations added approximately 5.0 million persons to the population total, 400,100 persons to the HCV antibody-positive total, and 258,600 to the HCV RNA-positive total. We estimated that overall in the United States 4,101,200 persons had HCV antibody and 2,386,100 persons were currently infected with HCV during 2013-2016.
One study of homeless persons attending a Federally Qualified Health Center reported an HCV antibody prevalence of 14.7%; HCV RNA prevalence was estimated at 10.8% (Table 3).
The literature search for hepatitis C prevalence data for incarcerated populations and homeless populations yielded 2,432 unique articles, of which only eight met the inclusion criteria (Table 2). Seven studies of incarcerated persons reported HCV prevalence, with HCV antibody prevalence ranging from 11.9% to 20.6%. Of these, four studies reported HCV RNA prevalence ranging from 9.1% to 15.2%; for the other three studies, HCV RNA prevalence was calculated by multiplying the reported HCV antibody prevalence by the 57.5% of HCV antibody-positive persons with HCV RNA from the 2013-2016 NHANES data (Table 3). The estimated mean HCV antibody prevalence was 16.1%, and the estimated mean HCV RNA prevalence was 10.7%.
During 2013-2016, the estimated NHANES HCV antibody prevalence among persons aged 18 years or above was 1.5% (95% CI, 1.3%-1.8%), corresponding to approximately 3.7 million persons (95% CI, 3.1 million to 4.4 million persons) with past or current HCV infection in the US noninstitutionalized civilian population. The estimated NHANES HCV RNA prevalence among persons aged 18 years or above was 0.9% (95% CI, 0.7%-1.0%), corresponding to approximately 2.1 million persons (95% CI, 1.8 million to 2.5 million persons) with current HCV infection in the US noninstitutionalized civilian population.
Abstract
Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States, causing substantial morbidity and mortality and costing billions of dollars annually.
To update the estimated HCV prevalence among all adults aged ≥18 years in the United States, we analyzed 2013-2016 data from the National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of HCV in the noninstitutionalized civilian population and used a combination of literature reviews and population size estimation approaches to estimate the HCV prevalence and population sizes for four additional populations: incarcerated people, unsheltered homeless people, active-duty military personnel, and nursing home residents.
We estimated that during 2013-2016 1.7% (95% confidence interval [CI], 1.4-2.0%) of all adults in the United States, approximately 4.1 (3.4-4.9) million persons, were HCV antibody-positive (indicating past or current infection) and that 1.0% (95% CI, 0.8-1.1%) of all adults, approximately 2.4 (2.0-2.8) million persons, were HCV RNA-positive (indicating current infection).
This includes 3.7 million noninstitutionalized civilian adults in the United States with HCV antibodies and 2.1 million with HCV RNA and an estimated 0.38 million HCV antibody-positive persons and 0.25 million HCV RNA-positive persons not part of the 2013-2016 NHANES sampling frame.
Conclusion: Over 2 million people in the United States had current HCV infection during 2013-2016; compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while RNA prevalence may have decreased, likely reflecting the combination of the opioid crisis, curative treatment for HCV infection, and mortality among the HCV-infected population; efforts on multiple fronts are needed to combat the evolving HCV epidemic, including increasing capacity for and access to HCV testing, linkage to care, and cure.
Abbreviations
• ACS
• American Community Survey
• AI/AN
• American Indian/Alaska Native
• CI
• confidence interval
• DAA
• direct-acting antiviral
• HCV
• hepatitis C virus
• MEC
• Mobile Examination Center
• NCHS
• National Center for Health Statistics
• NHANES
• National Health and Nutrition Examination Survey
Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States despite being underdiagnosed.1-3 Highly efficacious, all-oral direct-acting antiviral (DAA) therapy has revolutionized hepatitis C treatment within the past decade, dramatically improving cure rates over previous treatment modalities.4-6 Access to these therapies, however, is compromised by the high proportion of HCV-infected persons unaware of their status and, for those who have been diagnosed, insurer-implemented treatment restrictions related to concerns regarding the costs of HCV medications. Persons with untreated chronic HCV infection, as well as those who have been cured but still have advanced HCV-associated disease, are at risk for hepatic fibrosis, cirrhosis, and hepatocellular carcinoma; and HCV infection remains one of the leading causes of liver transplantation in the United States.7, 8 Nationwide, during 2012-2013, the annual number of HCV-related deaths exceeded the total number of deaths reported to the Centers for Disease Control and Prevention associated with the 60 other nationally notifiable infectious diseases combined.9
The prevalence of current HCV infection (indicated by HCV antibody positivity and RNA positivity) in a given population at a particular time depends on several factors: the number of people with existing chronic HCV infection (defined as detectable HCV RNA at least 6 months following acute infection), the number of people with incident HCV infection, the number of people cured of HCV infection (through spontaneous clearance or treatment), and the number of deaths among persons with chronic HCV infection, regardless of whether mortality is attributed to complications of HCV infection. An accurate estimate of hepatitis C prevalence can inform public health interventions and resource allocation strategies aimed at reducing the health burden and economic costs caused by hepatitis C in the United States.
The National Health and Nutrition Examination Survey (NHANES) combines interviews and physical examinations to assess the health and nutritional status of adults and children in the United States and to determine the prevalence of major diseases and disease risk factors.10 A 2014 analysis of NHANES data from 2003-2010 estimated that 3.6 million persons (95% confidence interval [CI], 3.0 million to 4.2 million persons) were HCV antibody-positive, indicating past or current HCV infection; of these, approximately 2.7 million (95% CI, 2.2 million to 3.2 million persons) were HCV RNA-positive, indicating current HCV infection of 1.0% (95% CI, 0.8%-1.2%) among the noninstitutionalized civilian US population aged ≥6 years.11 A 2015 brief report using NHANES data from 2011-2014 estimated current HCV infection of 0.9% (95% CI, 0.6%-1.2%) among US adults aged ≥18 years but did not report an estimate of HCV antibody positivity.12
While the NHANES national probability sample provides the best available measurement of HCV prevalence in the general US population, its sampling frame is the noninstitutionalized, civilian population of the United States; consequently, NHANES underestimates the true prevalence of HCV in the United States because it excludes certain populations known to have high HCV prevalence from its sampling frame. In 2015, researchers estimated that an additional 1.0 million persons (range 0.4 million to 1.8 million) in high-risk population groups unaccounted for by NHANES 2003-2010 data were HCV antibody-positive, of whom 0.8 million (range 0.3 million to 1.5 million) were chronically infected.13 These estimates suggested that in the United States during 2003-2010 4.6 million persons had HCV antibody and 3.5 million persons were living with current HCV infection. More recent estimates of HCV RNA prevalence are expected to be lower as more people are being cured because of improved HCV treatments; further, because the population in the United States is aging14 and death rates increase with age, many persons in the age cohort at highest risk for chronic infection, those born during 1945-1965,15 are dying of HCV-related and other causes. However, incident HCV infections linked to the opioid crisis and other drug use have simultaneously increased the overall prevalence of persons ever infected with HCV in the United States,16 potentially offsetting these expected reductions in HCV prevalence.
To provide an estimate of HCV prevalence among adults aged ≥18 years in the United States, we combined estimates of prevalence in the noninstitutionalized civilian population from NHANES 2013-2016 data with modeled estimates for four additional populations that were not sampled by NHANES.
Discussion
The purpose of our study was to provide an updated estimate of HCV prevalence among adults in the United States that would include persons in high-risk populations not part of the NHANES sampling frame. We estimate that during 2013-2016 in the United States 1.7% of all adults, or approximately 4.1 million persons, were HCV antibody-positive and that 1.0% of all adults, or approximately 2.4 million persons, were HCV RNA-positive. Our findings suggest that the 2013-2016 US HCV prevalence estimate derived from NHANES alone underestimates the actual number of HCV antibody-positive persons by approximately 0.38 million persons and the number of HCV RNA-positive persons by approximately 0.25 million persons.
Our analysis of NHANES data indicates an HCV antibody prevalence of 1.5% (3.7 million persons) during 2013-2016, higher than the previous NHANES estimate of 1.3% (3.6 million persons) during 2003-2010 that was produced using data collected before the 2013 revision of the NHANES HCV protocol.11 While it is possible that some of this increase is due to the change in the NHANES laboratory protocol, it also likely reflects the changing epidemic of HCV infection in the United States.1, 37, 38 From 2006 through 2012, state surveillance data from central Appalachia (Kentucky, Tennessee, Virginia, and West Virginia) demonstrated a 364% increase in the number of acute HCV infections among persons ≤30 years old.38 Furthermore, from 2011-2014, commercial laboratory data indicated a 22% increase in national rates of HCV detection among women of childbearing age.39 Overall, the number of incident hepatitis C cases reported in the United States through the National Notifiable Diseases Surveillance System increased 38.8% from 2013 through 2016, most markedly among those 20-39 years old, although increases occurred among adults of all ages.1
Our findings suggest an estimated HCV RNA prevalence in the noninstitutionalized civilian adult US population of 0.9% (2.1 million persons; 95% CI, 1.8 million to 2.5 million persons) during 2013-2016, similar to the NHANES estimate of 0.9% for 2011-201412 and lower than the previous NHANES estimate of 1.0% (2.7 million persons; 95% CI, 2.2 million to 3.2 million persons) during 2003-2010.11 Although the 2013 change in the NHANES HCV protocol may have played a role, the difference in these two estimates of current HCV infection is likely due to a combination of successful HCV treatment through oral DAA therapy and continued mortality (HCV-associated and all-cause).
While current therapies are highly efficacious, many populations have limited access to HCV testing, care, and treatment services. A recent systematic review of the literature indicated that only half of those infected with chronic HCV were diagnosed and aware of their infection, with only a proportion linked to care (43%), prescribed HCV treatment (16%), and achieving cure (9%).40 In the Chronic Hepatitis Cohort Study, only 5.7% of patients with HCV infection potentially eligible for treatment initiated a DAA regimen prescribed in 2014.41 Kanwal et al. reported slightly higher treatment rates at the Veterans Administration, where 10.2% of the nearly 150,000 patients with chronic HCV infection seen during the first 16 months of the DAA era received treatment.42
Encouragingly, oral DAA therapy uptake has increased since the medications were first licensed. At the Veterans Administration specifically, 62,290 veterans completed oral DAA treatment between January 1, 2014, and September 30, 2016; and the Veterans Administration estimates that an additional 59,200 veterans will be cured from 2017 through 2018.43, 44 These data suggest that successful treatment, while contributing to the decline in current HCV infections, does not entirely account for the decrease observed in NHANES-estimated current HCV infection. Unfortunately, continued mortality contributes to the changes in HCV prevalence. During 2016 in the United States, 18,153 hepatitis C-related deaths were reported to the National Vital Statistics System, representing a 6.3% decrease from 2013.1 A recent analysis demonstrated that HCV is substantially underreported on death certificates (even when the main cause of death is liver-related), suggesting that the approximately 20,000 death certificates that included documentation of HCV annually during the study period underestimate mortality in chronically HCV-infected persons.45 Additionally, as the population (adults born during 1945-1965, in particular) ages, deaths from competing, non-HCV-related causes contribute to a decrease in the overall prevalence of HCV infections.
Ultimately, given the rise in the number of persons with serologic evidence of an HCV infection in the past and the decline in the proportion of those persons currently infected with HCV, it is likely that successful treatment played an important role in the decrease in current HCV infection among the US noninstitutionalized civilian population. We estimated that 4.1 million persons were ever infected with HCV and approximately 2.4 million were currently infected, suggesting that about 1.7 million had cleared the infection. These 1.7 million adults either cleared the infection spontaneously or were cured through antiviral treatment. Some 15%-40% of infected persons resolve HCV infection spontaneously; women, younger persons, and those with certain immune response gene variants are more likely than other persons to clear HCV spontaneously.46, 47 Hundreds of thousands have likely been cleared through treatment and cure of their infection. An HCV drug manufacturer estimates that at least 673,000 people in the United States initiated an HCV treatment regimen during 2013-2016 alone.48
Compared with a previous estimate of the total US hepatitis C prevalence, our analysis identified lower HCV prevalence and fewer unenumerated HCV infections in populations not part of the NHANES sampling frame.13 According to our estimates, 0.38 million HCV antibody-positive and 0.25 million HCV RNA-positive persons from populations not part of the NHANES sampling frame should be added to the HCV prevalence estimate generated using 2013-2016 NHANES data alone. Several factors contribute to these differences. The overall additional population size is smaller in our analysis (5.0 million persons) compared with a previously published analysis because we concluded that people living in American Indian/Alaska Native (AI/AN) areas (C. Ogden, personal communication, May 30, 2018), people hospitalized for less than the 8-week duration of the NHANES sampling period, and sheltered homeless people were included in the NHANES sampling frame and therefore did not include them in our analysis of additional populations.13 This combined with the lower HCV prevalence reported in recent literature for incarcerated populations (16.1% HCV antibody prevalence in recent literature versus 23.1% HCV antibody prevalence in previous literature) and homeless populations (14.7% versus 32.1% HCV antibody prevalence) accounts for the reduction in unenumerated HCV infections in additional populations in our analysis.13
Our analysis had several limitations. First, the number of HCV-positive NHANES participants during 2013-2016 is small (n = 185 antibody-positive, n = 117 RNA-positive), even in this large nationally representative sample (n = 12,105 participants aged 18 years and older, of whom n = 10,857 were tested for HCV); although NHANES uses extensively tested protocols to encourage participation even in sensitive aspects of the study, if participants who did not participate in the examination component (n = 446), did not undergo HCV testing or provide a blood sample sufficient to yield conclusive HCV test results (n = 789), or opted not to participate in NHANES at all (n = 6,715, or 37% of, selected participants aged 20 years and above during 2013-2016) were disproportionately persons who had previously or concurrently injected drugs, NHANES may underestimate HCV prevalence even in the noninstitutionalized civilian population. However, one study, based on a dynamic model of HCV infection among the NHANES-eligible population from 2001 and beyond, estimated that 1.84 million noninstitutionalized people were HCV RNA-positive in the United States in 2015.49 This estimate is only 15% lower than our estimate of HCV RNA prevalence in the noninstitutionalized civilian population during 2013-2016. Second, the effect of the NHANES change in laboratory testing methods on HCV antibody and RNA prevalence estimates before and after 2013 could not be assessed within the NHANES population, and thus any comparison of our current findings with previous estimates should be interpreted with caution. The change in NHANES protocol could potentially be a cause of higher HCV antibody prevalence in the current study; however, a full crossover comparison study using surplus NHANES sera to evaluate the effect of the 2013 change in the NHANES HCV protocol could not be conducted due to ethical considerations of potential clinically relevant findings from such a study, and lack of availability of RIBA test kits prevented a prospective crossover study among NHANES participants after 2013. Third, none of the studies identified through our literature review were designed to generate nationally representative estimates of HCV prevalence in the additional populations. We excluded studies that selectively sampled higher-risk subpopulations (e.g., people who inject drugs) in an attempt to mitigate the potential lack of representativeness. Furthermore, a recent study published after our literature review was closed estimated that 18% of Americans who are in prison at any given time have antibodies to HCV,50 slightly above our estimate, suggesting that the studies included in our analysis for the incarcerated population provide a credible HCV prevalence estimate for this additional population. The single study of the homeless population, however, may not be representative of this population nationwide. Fourth, we performed a sensitivity analysis on the homeless population estimates. Had we included the 263,500 sheltered homeless adults in 2016 in our analysis, we would have added 38,900 HCV antibody-positive persons and 28,500 HCV RNA-positive persons to our estimates. Fifth, because the source studies were not conducted for the purpose of synthesis into a national estimate, the application of meta-analytic and other statistical procedures to create CIs for additional populations should be interpreted more cautiously than CIs based on NHANES alone. Sixth, because people living in AI/AN areas could potentially be undersampled by the NHANES sampling frame, we performed a sensitivity analysis, applying a literature-based HCV prevalence estimate specific to people living in AI/AN areas,51 to determine the HCV prevalence among this population. We estimate that there were approximately 125,000 HCV RNA-positive adults living in AI/AN areas during 2013-2016. This estimate likely represents the upper limit of current HCV infections in AI/AN areas during this time period. Finally, when we applied the 2013-2016 NHANES HCV RNA prevalence to the additional populations, we conferred to them the spontaneous clearance and treatment levels of the noninstitutionalized civilian population. This assumption may not be accurate (i.e., treatment levels are likely to be lower in the additional populations than in the noninstitutionalized civilian population) and could have resulted in underestimation of the prevalence of current HCV infection in the three incarcerated population studies that did not report HCV RNA prevalence; however, HCV antibody prevalence would be unaffected. We performed a sensitivity analysis applying the mean HCV RNA prevalence among those who tested antibody-positive from the four incarcerated population studies that reported HCV RNA prevalence to the three incarcerated population studies that did not report HCV RNA prevalence; the mean HCV RNA prevalence for the incarcerated population increased from 10.7% (when the 2013-2016 NHANES HCV RNA prevalence was applied) to 11.6%, a difference of 20,700 HCV RNA-positive persons overall (data not shown).
In summary, we estimate that during 2013-2016 in the United States approximately 4.1 million adults had evidence of past or current HCV infection, of whom approximately 2.4 million were currently infected with HCV. Compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while HCV RNA prevalence may have decreased, likely reflecting the impact of the opioid crisis on HCV incidence, use of effective treatment regimens, and continuing mortality among the HCV-infected population. Forthcoming work will include state-level estimates of hepatitis C prevalence using this methodology as well as delve deeper into the NHANES data to examine differences by group and the proportion of those aware of their infection and receiving care. Comprehensive and accurate estimates of HCV prevalence can guide health interventions and resource allocation to link chronically infected persons to care, treatment, and ultimately cure. Continued efforts to reduce the burden of HCV infection will require improved interventions to prevent infections, expanded testing to find undiagnosed persons, and strategies to ensure treatment so that HCV-infected persons are promptly cured.
| |
| |
| |
|
|
|
