Summary

Every year, hepatitis B and C account for more than 1 million deaths worldwide, 78 percent of the world’s hepatocellular carcinoma, and more than half of all fatal cirrhosis. In 2013 viral hepatitis, of which hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common types, surpassed HIV and AIDS to become the seventh leading cause of death worldwide.

The world has the tools to prevent hepatitis B and cure hepatitis C. A vaccine against HBV confers greater than 95 percent immunity in three doses; new direct-acting antiviral treatments for chronic hepatitis C can cure¹ infection in more than 95 percent of patients. Together these advances have encouraged a global momentum for action against the epidemics of hepatitis B and C. The World Health Organization (WHO) has made viral hepatitis a priority; the United Nations Sustainable Development Goals mention combatting viral hepatitis. At the 2016 World Health Assembly, member states will consider a resolution to eliminate hepatitis B and C by 2030.

The United States has clear goals for combatting hepatitis B and C. The interagency action plan for viral hepatitis emphasizes increasing diagnosis of HBV and HCV, ending mother-to-child transmission of hepatitis B, and reducing incidence of HCV. The goals are the special purview of the Divi-

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¹ In this document sustained virologic response is used synonymously with cure. When interferon treatments were standard of care for hepatitis C this was defined as negative viral load 24 weeks after cessation of therapy, though with direct-acting antivirals negative viral load after 12 weeks is considered sustained virologic response.

sion of Viral Hepatitis at the Centers for Disease Control and Prevention (CDC) and the Office of Minority Health in the Department of Health and Human Services (HHS). Both offices are involved in the global discussion about hepatitis B and C elimination and requested that the National Academies of Sciences, Engineering, and Medicine convene a consensus committee to analyze the question of hepatitis B and C elimination in the United States. The sponsors commissioned this work in two parts. The first task, addressed in this report, was to determine if national elimination of hepatitis B and C is a feasible goal and to describe barriers to meeting this goal. The second phase of the project will set a strategy and recommend action to eliminate the public health problem of hepatitis B and C, and will end in a consensus report by the same committee, to be published in 2017.

This report discusses the feasibility of eliminating the public health problem of hepatitis B and C from the United States. Though historically disease elimination refers to complete termination of any incident infections in a population, elimination of a public health problem can be a less absolute goal. The WHO has accepted a non-zero target in its work against viral hepatitis. The organization’s provisional target is a 90 percent reduction in incidence and a 65 percent reduction in mortality by 2030. These are global targets, however. The disease burden and epidemiological features of HBV and HCV in individual countries should determine the national elimination strategy.

Perfect vaccination could eradicate HBV, but it would take two generations. In the meantime, there is no cure for the millions of people already infected. Conversely, there is no vaccine for HCV. New direct-acting antivirals can cure nearly all chronic infections, though cost of these drugs and the burden of undiagnosed HCV infection mean that only a small fraction of all chronically infected people can access them. The committee considered these questions in its assessment of the feasibility of hepatitis B and C elimination in the United States, weighing the motivational power of a disease elimination goal against the danger of over-promising. It concluded that hepatitis B and C could both be eliminated as public health problems in the United States, but that this would take considerable will and resources; disease control might be more manageable in the short-term. (Disease control, in the committee’s deliberations, refers to a reduction in the incidence and prevalence of hepatitis B and C and their sequelae with ongoing control measures, while elimination refers to cessation of transmission in the United States, allowing that the disease itself may remain, but particularly undesirable clinical manifestations prevented entirely.) For the committee’s purposes, a public health problem may be defined as a disease that by virtue of transmission or morbidity or mortality commands attention as a major threat to the health of the community.

Broadly speaking, eliminating the public health problem of hepatitis B

and C in the United States is a matter of ending transmission and preventing morbidity and mortality among people with chronic infection. There will be room for disagreement as to exactly what constitutes a public health problem, however. To some extent, that determination must be informed by accurate information on the magnitude and distribution of infections in the population. Hepatitis B and C are both largely asymptomatic until the late stages. Less than a third of people with chronic hepatitis B and about half of those with chronic hepatitis C are aware of their infection. Clinical management for these conditions requires designated staffing case management and strong laboratory infrastructure. Viral hepatitis is not a well-funded target for public health surveillance, however. The CDC only funds seven jurisdictions for comprehensive viral hepatitis surveillance. It is difficult to even count deaths attributable to HBV and HCV, as death certificates usually only note cirrhosis or hepatocellular carcinoma without mention of the root cause.

Both HBV and HCV tend to be asymptomatic until their later stages. They can both end in liver fibrosis, cirrhosis, and cancer. Otherwise, the diseases are very different. Therefore, this report discusses HBV and HCV separately, and identifies separate critical factors for supporting their elimination.

ELIMINATING THE PUBLIC HEALTH PROBLEM OF HEPATITIS B

After analyzing the problem of hepatitis B in the United States, the committee concluded that control is feasible in the relatively short term. Eliminating the public health problem of hepatitis B will take more time, and require considerable public will, resources, and attention to the barriers mentioned in Table S-1.

Ending Transmission of HBV

The first step in eliminating hepatitis B is ending transmission of the virus. HBV is transmitted three main ways: from an infected mother to her child, from direct contact with infected blood, or from unprotected sex with an infected partner. All could be prevented with universal immunization; HBV vaccine confers long-lasting, 95 percent immunity in three doses. HBV vaccine coverage is good in most of the world. About 82 percent of the world’s infants receive all three doses, but coverage of the birth dose, essential for ending perinatal transmission, is only 38 percent. Support for immunization, especially in the HBV endemic countries of Asia and sub-Saharan Africa could do much to reduce the world’s pool of chronic hepatitis B. Action in endemic countries would also reduce future disease burden in the United States since most chronic HBV infections are imported.

A dose of HBV vaccine at birth and completion of the full vaccine series can help prevent transmission of HBV from mother to child, but better protection is offered by combining the vaccine with hepatitis B immune globulin within 12 hours of birth. It is therefore important to identify women with chronic HBV infection during pregnancy so their babies can receive full and prompt prophylaxis and post-vaccination serologic testing. Mother-to-child transmission of hepatitis B is rare, but not unknown, in the United States. Better screening and surveillance could help avert the 800 to 1,000 infections per year passed from mother to child.

There is room for improvement in the general childhood HBV vaccination in the United States. Only about 64 percent of infants receive the HBV vaccine within 1 day of birth and about 72 percent receive it within the first 3 days, but childhood catch-up is possible. Vaccination of adults is more complicated, as there is no comprehensive system for immunization after school age. Targeting high-risk populations, through routine vaccination at prisons or in sexually transmitted disease clinics, might be an efficient way to reach HBV-susceptible adults.

Reducing Morbidity and Mortality Attributable to Chronic Infection

The at least 700,000 to 1.4 million people in the United States with chronic HBV infection need lifelong monitoring for disease progression. In the immune tolerant phase, hepatitis B does not require antiviral therapy, but still needs regular monitoring to ensure the patient has not entered the immune active phase when treatment is beneficial. Immune active hepatitis B is treated with highly potent antivirals with low risk of resistance. Treatment is not curative, but sustained treatment response prevents disease progression and deaths from cirrhosis and liver cancer. Once antiviral therapy is started, it is not discontinued lightly. Drug cessation can cause HBV reactivation, liver flares, and hepatic decompensation. The clinical management of HBV infection also requires screening for hepatocellular carcinoma and monitoring co-factors of liver disease progression, such as excessive alcohol intake and use of herbal or dietary supplements and acetaminophen. Providers have to screen for liver cancer, and choose appropriate treatments to control chronic hepatitis B, but none of the treatments currently available cures the infection.

Chronic or resolved HBV infection in patients who are not on antivirals can reactivate when drugs used to treat cancer, organ transplantation, or autoimmune disease suppress the immune system. Reactivation can lead to acute liver injury, liver failure, and death. Antiviral prophylaxis can reduce this risk, but it is not clear in which patients or for how long, nor is the relationship between reactivation and different chemotherapy regimens.

Barriers to Hepatitis B Elimination

There are various barriers to eliminating the public health problem of hepatitis B in the United States that would affect both ending transmission and reducing the complications of chronic infection. Limited disease surveillance is one of these barriers. If state and local health offices cannot identify acute or chronic infections, then there will be an incomplete understanding of the epidemic and the strategies to combat it.

There are many serum markers of hepatitis B infection. Full characterization of infection requires analysis of a panel of indicators. Inconsistencies in laboratory testing can impede the investigation of suspected outbreaks. In some health departments surveillance includes follow-up with the infected person to facilitate testing and vaccination of his or her close contacts, although such follow-up exceeds the staff capacity at many health departments. This strategy could be more effective if vaccine registries were designed to share data across state and local boundaries, something not currently possible.

Feelings of shame and depression in HBV-infected people can also hold back progress on elimination. Fear of a positive test result can cause people to avoid screening. HBV stigma is particularly severe among East Asians, an essential target group for screening and treatment. Education can affect social norms and help reduce stigma, but such a process takes time. In the meantime, testing and screening for the HBV, especially among people born abroad, will be essential. Screening foreign-born people who are uninsured or undocumented presents challenges, however. Foreigners must reside in the United States for 5 years to qualify for many state Medicaid programs; the Affordable Care Act also restricts care for temporary residents and undocumented arrivals. Screening puts an onus on the screener to link infected patients to care, something that some HBV-infected people will not have access to.

It is difficult to ensure that anyone identified through HBV screening campaigns is enrolled and retained in care. The burden of HBV care lies largely on the managing provider, some of whom are not familiar with the long term management of chronic hepatitis B. Electronic patient files and team-based care have the potential to improve care, but more research is needed to define how this could work. More research on hepatitis B would benefit any elimination strategy. Important research topics include reactivation and development of curative therapy.

ELIMINATING THE PUBLIC HEALTH PROBLEM OF HEPATITIS C

After analyzing the problem of hepatitis C in the United States, the committee concluded that control is feasible in the relatively short term.

Eliminating the public health problem of hepatitis C will take more time, and require considerable public will, resources, and attention to the barriers mentioned in Table S-2.

Ending Transmission of HCV

HCV is transmitted through contact with infected blood, and, less commonly through sexual contact or from mother to child. There is no vaccine for HCV, so preventing transmission becomes a matter of both reducing the likelihood that someone with hepatitis C will transmit the virus and reducing the risk that someone uninfected will contract it. The people at greatest risk of contracting HCV are young and inject drugs. This can be a difficult group to reach, but some evidence suggests that programs such as needle exchange can reduce their vulnerability. Preventing substance use disorders could also lower transmission by reducing the number of people at risk for contracting the virus. Even delaying HCV infection can provide valuable time to change the course of addiction in young drug injectors. The scientific literature offers many examples of harm reduction (programs such as needle exchange) for people who inject drugs, but most of these programs took place in densely populated cities. Injection drug use is becoming more common in rural areas and small towns, adapting programs to these settings while still reaching enough people to have meaningful effect on behavior could be challenging.

Treating people who inject drugs with curative HCV therapies could also reduce transmission, and elicit a reduction in disease prevalence of 20 to 80 percent. But only a fraction of people with chronic HCV infection actually transmit the virus. People most likely to transmit the virus are actively injecting drugs; they are young and frequently imprisoned. Although HCV passes only infrequently from mother to child, pregnant women can transmit the virus to their infants. Among people with HIV and HCV, the risk of sexual transmission of HCV rises, so people infected with both viruses are also considered high risk. In general, the people driving most transmission are otherwise healthy, so curing their infection prevents no immediate deaths. Preventing imminent deaths means treating people at risk for cirrhosis. These tend to be older people, who are far less likely to pass the virus through drug use or sexual contact, and are usually beyond childbearing age. Though curative treatment can both prevent deaths from HCV and interrupt transmission, meeting these goals requires attention to different populations.

Eliminating Chronic HCV Infection

Chronic hepatitis C disproportionately affects people born between 1945 and 1965 and African-Americans, as well as people in jail and prison. Better screening and referral to treatment could help reach more infected patients, many of whom would be candidates for direct-acting antiviral treatment to eliminate their chronic infection. These drugs are expensive. Both Medicaid and private insurers have responded to the cost by restricting access. The restrictions complicate the provider’s job and may harm the patient–provider relationship.

The direct-acting agents are new and the possibility of drug resistance is not well understood. Poor adherence to treatment may cause drug resistance and reduce the likelihood of treatment response.

Reducing Morbidity and Mortality from Hepatitis C

HCV infection substantially raises risk of death, especially when the infection has progressed to cirrhosis. In the near term, cirrhotic patients have the most to gain from HCV cure, as the nature of their disease puts them at the highest risk of death. Curing HCV infection in patients with decompensated cirrhosis can avoid the need for liver transplantation; cure after transplant prolongs graft survival. Progression of HCV is linked to severity of fibrosis, something that is difficult to measure. Liver biopsy is considered the most accurate measurement, but it is an invasive and expensive procedure that yields, at best, incomplete information. Certain patient characteristics also predict progression to fibrosis. Alcohol use, fatty liver disease, diabetes, and dyslipidemia can all speed progression to fibrosis, but estimating any patient’s risk of fibrosis is uncertain because of poorly understood interactions between the virus and host.

Curing HCV before progression to advanced fibrosis can prevent deaths from chronic infection. New curative treatments can elicit sustained virological response in 94 to 99 percent of patients, likely reducing the risk of cirrhosis and hepatocellular carcinoma. Sustained virological response can in turn restore liver function in patients with decompensated cirrhosis. Ending illness and deaths from hepatitis C depends on both stopping the disease’s progression in its early stages, and, ideally, reversing the course of advanced disease.

Barriers to Hepatitis C Elimination

As with HBV, some of the barriers to elimination of HCV would hold back progress across the board, be it in ending transmission, eliminating chronic infection, or reducing the complications of chronic infection. In-

complete surveillance is the first example of such a barrier. Few jurisdictions in the United States have funding for viral hepatitis surveillance, so there is little information about the true incidence and prevalence of infection. Identifying acute cases through surveillance is an imprecise process; the case definition required for inclusion national statistics may be overly restrictive. Reporting of chronic hepatitis C is more straightforward, but the volume of infections and the amount of laboratory testing required to confirm them produces more information than the health department can currently capture. Chronic hepatitis C requires long-term follow-up, something infectious disease surveillance systems are not always designed to track.

Prompt identification of hepatitis C cases is challenging in part because the disease is largely asymptomatic until its later stages. Universal screening among people born between 1945 and 1965 could give a better understanding of the true disease prevalence, but so far, the screening guideline is observed more in the breach than in practice. While people born between 1945 and 1965 account for the majority of chronic hepatitis C in the United States; most new HCV infections in the United States are associated with injection drug use. People who inject drugs are difficult to reach with traditional screening methods; surveys tend to systematically undercount them and other marginalized groups including the homeless and incarcerated. Community screening could improve the proportion of chronically infected people diagnosed, but requires a way to enroll patients in care with minimal losses to follow-up. Managing and retaining HCV patients in care over time is challenging, especially for primary care physicians who are already working at full capacity. Strategies to improve patient retention could include the use of patient navigators and attention to Wagner’s chronic care model.

Despite the efficacy of direct-acting agents, only about 1 out of every 10 chronically infected patients receives them. The prices of drugs are high, putting pressure on the budgets of public and private insurers. Insurers have responded to these prices by restricting access. The restrictions are not supported by current treatment guidelines, and appear motivated entirely by cost. Even with restrictions in place, these drugs accounted for a third of the sharp rise in prescription drug spending between 2013 and 2014. Such dramatic increases are uncommon and make insurers reluctant to provide unrestricted access to these expensive products.

The new HCV drugs are expensive, but they are still cost-effective compared to older interferon-based therapies. The benefits of treatment to both society and to the health system still outweigh the costs. Eliminating chronic infections is possible, and treatment would do much to reduce transmission as well, but would require near universal access to treatment. Such access appears unfeasible in the current pricing and policy environment.

Through its association with drug use and incarceration, HCV infection carries a social stigma. This stigma can cause feelings of shame and depres-

sion in chronically infected people, leading them in turn to avoid medical care, a poor outcome for the patients and for society. Stigma can also prevent HCV from being a public priority. Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high and the staff time required to manage an inmate in treatment often far exceed the available resources.

Although ending the public health problem of hepatitis B and C in the United States is feasible, it is not necessarily likely without considerable attention to the barriers discussed in this report. The strategy needed to address the critical factors and mitigate the barriers laid out in Tables S-1 and S-2 will be discussed in phase two of this project, in a report to be released in 2017.

TABLE S-1 The Feasibility of Eliminating Hepatitis B as a Public Health Problem in the United States with Critical Factors for Success and Crosscutting Problems

NOTE: cccDNA, covalently closed circular DNA; HBV, hepatitis B virus.

TABLE S-2 The Feasibility of Eliminating Hepatitis C as a Public Health Problem in the United States with Critical Factors for Success and Crosscutting Problems

NOTE: HCV, hepatitis C virus.

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