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Among the blood-borne chronic viral infections, hepatitis B virus (HBV) infection is one that is not only treatable but also preventable by provision of vaccination. Despite the availability of HBV vaccine for the last 15 years, more than 1.25 million individuals in the USA have chronic HBV infection, and about 5,000 die each year from HBV-related complications. From a societal perspective, access to treatment of chronic viral infections, like HIV and viral hepatitis, is highly cost-effective and has lasting benefits by reducing risk behaviors, morbidity, mortality, as well as disease transmission in the community. Individuals in correctional facilities are specially predisposed to such chronic viral infections because of their high-risk behaviors. The explosion of incarceration in the USA over the last few decades and the disproportionate burden of morbidity and mortality from chronic infections among the incarcerated have put incredible strains on an overcrowded system that was not originally designed to provide comprehensive medical care for chronic illnesses. Recently, there has been a call to address medical care for individuals with chronic medical conditions in correctional settings, including those with infectious diseases. The economic and public health burden of chronic hepatitis B and its sequelae, including cirrhosis and hepatocellular carcinoma, is felt most prominently in managed care settings with limited budgets, like correctional facilities. Prevalence of HBV infection among the incarcerated in the USA is fivefold that of the general population. We present a review of diagnosis, prevention, and the recently streamlined treatment guidelines for management of HBV infection in correctional settings, and discuss the implications and public health impact of these measures.
In the USA, at year end 2006, over 7.2 million people were under correctional supervision and over 2 million were housed within correctional institutions, resulting in 3.4% of all US adult residents (one in every 31 adults) being under correctional supervision.1 The USA imprisons its population at the highest known rate in the world, at 751 per 100,000 in 2006, indicating the country’s formidable social policy of imprisonment and the huge public health impact of prisoners’ health on communities at large.2
Inmates in correctional facilities bear a greater burden of chronic viral infections, substance use disorders, mental illness, and sexually transmitted diseases.3 Women prisoners are at additional risk for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as a consequence of being more likely to be drug users and engaging in commercial sex work.4 The most recent report of the burden of infectious diseases among prisoners and recently released individuals in the USA was presented to the Congress with data accurate to 1996, indicating disproportionately higher prevalence of chronic infections among these individuals than the general US population: HIV (ninefold higher), AIDS (sixfold), HCV (tenfold), HBV (fivefold), and tuberculosis (fourfold).5 Access to prevention and medical treatment during incarceration and continuity after release can provide lasting benefits to communities by reducing disease transmission and by facilitating rehabilitation.6,7
More than 2 billion people worldwide have been infected with HBV, of whom 360 million are chronically infected and are at an increased risk of liver-related sequelae, including cirrhosis, fulminant hepatic failure, hepatocellular carcinoma (HCC), and a 15–25% higher risk of premature death.8 In the USA, the prevalence of HBV infection (including persons with chronic infection and those with previous infection) was 4.9% in the third National Health and Nutrition Examination Survey (NHANES III, 1988–1994).9 The incidence of acute HBV infection has declined in the USA over the last 15 years because of routine HBV vaccination of infants. Still, in 2006, an estimated 1.25 million individuals had chronic HBV infection, and 46,000 new cases of HBV infection were estimated to have occurred in that year alone —2.4 times as many as the newly diagnosed cases of hepatitis C.10 It is estimated that up to 5,000 people die each year in the USA from HBV-related complications.
Up to 40% of all Americans with chronic viral hepatitis and approximately 30% of persons with acute HBV infection have been incarcerated.11 Among patients with acute hepatitis B reported to the CDC, 5.6% have a history of incarceration during the disease incubation period.12 HBV infection is known to be transmitted within correctional settings, and incidence rates have ranged from 0.82% to 3.8% per year.13,16 Outbreaks of HBV in correctional facilities have been well-documented.5,14–16 The source-patient as well as many of the infected inmates in these outbreaks were found to have subclinical infection, indicating the undetected burden of disease. Such subclinical transmission risk among the incarcerated population formed the basis of recommendation by CDC for HBV vaccination in correctional settings.
An accurate prevalence of HBV infection in US correctional facilities has not been ascertained for more than a decade.5 At that time, in 1996, HBsAg seroprevalence was ~2% among this population, as compared to the national prevalence of 0.4% and had been estimated based on two state studies in California (1994) and New York (1987–1997).17,18 The prevalence of serologic markers for current or past HBV infection among inmates ranges from 13% to 47%. Prevalence is higher among female prisoners (37–47%) than in men (13–32%).17,19 Upon release, susceptible inmates are often at increased risk for infection because they resume high-risk behaviors. A study of recidivist women reported an HBV seroconversion rate of 12.2/100 person-years between incarcerations, compared with estimated incidence of 0.03/100 person-years for the US population.19,20 Prisons are, therefore, important sites for detection of and vaccination against hepatitis B, particularly in women to prevent perinatal transmission of HBV infection to newborns. A survey of US correctional institutions confirmed the lack of routine HBV screening despite the public health mandate to vaccinate high-risk individuals as well as to identify and treat individuals with active HBV infection.21 Of the 35 states that responded to that survey, only two reported screening all their inmates routinely for hepatitis B immunity to determine requirement for vaccination. Two other states offered HBV vaccine to all inmates without routine screening.
After an initial incubation period of 1 to 4 months, 30% to 80% exposed adults develop symptomatic acute hepatitis B with fatigue, nausea, and occasionally jaundice.22 Laboratory testing reveals significant elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which normalize within 1 to 4 months in patients who recover. Serologic markers are diagnostic (Table 1).
Progression to chronic hepatitis is defined as persistence of elevated AST/ALT or HBsAg for more than 6 months and is seen in only 5% of immunocompetent adults infected with HBV.22 Persistence of HBsAg marks transmission risk of infection, which is markedly increased with HBeAg positivity. During the initial immunotolerant phase, serological markers of viral replication including HBsAg, HBeAg, and HBV DNA are seen, while AST/ALT are normal to mildly elevated. Subsequently, there is a prolonged immune-clearance phase of chronic active hepatitis (CAH) with normal to moderate elevation of AST/ALT and gradual reduction in the HBV DNA level. Spontaneous HBeAg seroconversion occurs at a rate of 10% to 20% per year in healthy adults and is marked by elevation of AST/ALT, with clinical worsening. Persons who have been exposed to HBV just before incarceration, therefore, may not develop clinical symptoms until some time after incarceration. These symptoms of lethargy, nausea, abdominal pain, and occasionally mild fevers may be mistaken for those of withdrawal from illicit drugs. Liver function tests and serological evaluation can help discern substance withdrawal from HBV infection in these inmates for appropriate management.
Less than 1% adult patients clear the HBsAg per year (known as HBsAg-seroconversion). In most, it persists but with undetectable HBV DNA. Even in these “healthy carriers”, there is underlying slow histopathological viral activity, with progressive fibrosis and increased risk for HCC.23 Patients with negative HBeAg and undetectable HBV DNA should therefore have regular follow-up until HBsAg-seroconversion occurs.45
Eight different genotypes of HBV (A–H) are known to date. In the USA, the commonest genotypes are A and C, followed by B and D.24 HBV genotype correlates to clinical outcome. For instance, genotype C increases the risk for HCC.25 Genotype B is associated with HBeAg seroconversion at a younger age,26 while genotypes A and B are associated with improved response to interferon therapy.27 To date, response to antiviral agents has not been correlated with HBV genotype.
HBV has the highest mutability among all DNA viruses. Certain mutations result in complete prevention or down-regulation of HBeAg production, thereby increasing the virulence. HBV strains with these mutations are known as Precore and Core Promoter mutants, respectively. Such mutants can result in failure of immunological attempts at HBeAg/Ab-seroconversion and cause relatively severe histopathological disease, albeit low HBV DNA levels. This plays a role in the determination of time for treatment initiation (Table 4). The risk of cirrhosis is higher in HBeAg-negative disease, with up to 29% cirrhotic at the time of initial presentation.28 HBV also develops mutations under selective pressure from antivirals, as outlined later.
The morbidity and mortality in chronic hepatitis B are directly related to the development of cirrhosis and HCC. Cirrhosis develops within 6 years in 30% of patients with moderate CAH and within 4 years in 50% of those with severe CAH.29 In patients with HBV-related cirrhosis, the probability of decompensation is 20% to 28% and that of HCC is 6%, 5 years after diagnosis.29 One large study found that the relative risk of HCC was 9.6 among patients with HBsAg alone and 60.2 among those with both HBsAg and HBeAg, as compared with those who were negative for both.30 Elevated serum HBV DNA level (≥10,000 copies/mL) is a strong risk predictor of adverse outcomes independent of HBeAg and serum ALT level, with a cumulative incidence rate of 14.9% for HCC and relative risk of 6.5 for cirrhosis at HBV DNA level of ≥1 million/mL.31,32 Co-infections with HIV, HCV, both HIV and HCV, and with HDV have been shown to increase the rates of cirrhosis and HCC.46 Host HLA type also predicts outcome of infection. HLA DR13 promotes a robust immune response with spontaneous clearance of HBV and HLA-DRB1*07 reduces the response to interferon therapy for HBV.33,34
Many adolescents and young adults are still not receiving vaccinations, despite recommendations for universal vaccination among persons aged ≤18 years35 and will likely put themselves at risk for HBV infection through sexual and drug-use behaviors.36 Such high-risk behavior is especially common in the incarcerated population.37 Transmission of blood-borne pathogens including HBV among inmates is known to occur during injection drug use, sharing tattoo paraphernalia and razor blades, fights, and consensual/nonconsensual sexual activity.38 HBV is known to be secreted in saliva and to survive on environmental surfaces for at least a week, with potential transmission by sharing contaminated personal use items such as razors and toothbrushes—all of which are in limited supply within correctional settings.39,40 Lack of easy access to condoms and needle-exchange programs enhances the risks involved in these settings.
Provision for both pre-exposure and post-exposure prophylaxis is required to maximize prevention of HBV transmission in correctional facilities. Recently updated recommendations of Advisory Committee on Immunization Practices (ACIP) include hepatitis B vaccination for all adults in high-risk individuals, including inmates of correctional facilities.41 The recommended vaccination schedule consists of three intramuscular doses of hepatitis B vaccine given at 0, 1, and 6 months. Better response to the vaccine in HIV-positive inmates can be ensured by giving the vaccine when CD4 cell counts are >200/µL and by giving double-dose vaccines.42,45 Post-exposure prophylaxis for non-occupational exposure (for inmates) depends on HBV vaccination/infection status of the exposed and source individuals (Table 2) and should be initiated as soon after exposure as possible to maximize the effectiveness.41 Pregnancy is not a contraindication for the hepatitis B vaccine. Vaccination of women inmates of reproductive age is of special significance to prevent perinatal HBV transmission. If universal vaccination is not implemented, vaccination of high-risk inmates could still bring about reasonable changes in the burden of disease and morbidity. For instance, inmates infected with HIV and/or HCV should be screened for HBV infection and, if found to be seronegative, should be vaccinated to prevent the accelerated hepatic fibrosis caused by HBV co-infection in these individuals.
The challenges for HBV vaccination vary between prisons and jails. While it is both cost-effective and feasible to screen and vaccinate prisoners due the longer period of incarceration, jails pose more challenging constraints with the high number of entrants and the rapid turnover of the population. In such settings, it may be useful to implement an accelerated immunization schedule (HBV vaccine at 0, 7, and 21 days or at 0, 1, and 2 months).43 Protective levels of antibody have been demonstrated after one (30–50%) or two (89%) doses of the vaccine.44
Treatment guidelines are continually evolving with expansion of knowledge about natural history and development of new therapies. Two sets of guidelines are commonly used, the AASLD practice guidelines45 and a treatment algorithm developed by a group of expert hepatologists in the USA.46
Candidacy for treatment initiation and choice of medications are determined by clinical and biochemical/serological evaluation (Table 3). The two sets of guidelines differ in cutoff limits for HBV DNA and ALT levels in determining treatment eligibility (Table 4). Both sets of guidelines make special note of the corrected upper limits of ALT at 30 IU/L for men and 19 IU/L for women. With growing evidence that progressive liver fibrosis can occur even with normal ALT levels, more experts recommend not basing treatment on ALT levels alone.31,32,46 Liver biopsy is most useful in patients for whom treatment eligibility is unclear and for patients older than 35–40 years of age with normal ALT levels, a group that may be at higher risk for fibrosis. If liver histopathology shows significant fibrosis in these individuals, treatment may be indicated even if ALT levels are low or within normal limits.
Several new and effective treatments for HBV infection have resulted in the ability to improve HBV treatment outcomes and potentially result in reduced transmission of HBV.47 Currently, seven therapeutic agents are approved for the treatment of adults with chronic hepatitis B in USA interferon alpha-2b, peginterferon alpha-2a, lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir.45 Tenofovir is the most recently added agent to this list, after it was approved for the treatment of chronic HBV infection by FDA in August, 2008. Clevudine and emtricitabine are fast gaining data to support approval as first line agents for treatment of HBV infection. Entecavir and tenofovir have superior efficacy and comparable safety to lamivudine and adefovir.48,49 Tenofovir is safe and efficacious in HBV-infected cirrhotic patients, too.50 In HBeAg-positive individuals, HBsAg loss occurs at rates of 3% and 5%, respectively, with tenofovir and entecavir.51,52 Interferons result in excellent HBsAg seroconversion rate (29%), but the rate of sustained virological response is lower (26%) and incidence of adverse effects higher.53
The overall duration of treatment for many patients is still uncertain, as none of the currently available agents eradicate HBV DNA indefinitely. In HBeAg-positive hepatitis, treatment is continued until ≥3–6 months after HBeAg seroconversion. Virologic response is sustained in 70–90% patients after treatment discontinuation. For HBeAg-negative infection, the duration of treatment is prolonged and indefinite. Medications with a high genetic barrier to resistance, e.g., entecavir, are therefore preferred. Early virologic response is defined as a decrease in HBV DNA level by ≥1 log 10 IU/ml at 12 weeks of treatment. HBV DNA level at 24 weeks of treatment is the best predictor of efficacy. Experts recommend assessing on-treatment virologic response every 3 months until sustained aviremia, and adding a more potent agent if response is inadequate.54 The risks and benefits of long-term treatment of chronic HBV infection are largely unknown at this time. Lamivudine and adefovir, the earliest antiviral agents used for HBV, have been shown to be safe and effective over prolonged periods of time but are riddled with development of breakthrough antiviral resistance.
Management of chronic HBV infection within correctional facilities needs to be supervised by physician experts, with careful and strategic patient selection and close monitoring. The evidence-based data that direct treatment guidelines are not derived from studies of inmate populations. Many of the critical studies involved East Asian populations, not largely represented in US jails and prisons. Expert evaluation is therefore required before making treatment decisions. Caution is required when planning premature discontinuation of treatment before adequate seroconversion has occurred. Severe acute exacerbation of hepatitis has been reported when patients discontinue anti-HBV agents. This is of special significance in inmates who are known to be poorly adherent to treatment. Medication reconciliation is important in this matter for inmates entering jails/prisons on treatment and those transferring between correctional facilities.
Monotherapy with lamivudine is associated with unacceptably high rates of resistance (14–32% per year and 70% after 4 years).55 In patients coinfected with HIV, this rate is higher (≤90% after 4 years).56 Lamivudine monotherapy is therefore not currently indicated for treatment of chronic hepatitis B, with the exception of pregnant patients. Lamivudine in combination with adefovir may be used in cirrhotic patients, who cannot tolerate pegylated interferon, entecavir, or tenofovir. Adefovir resistance develops in up to 3% of HBeAg-positive patients and 5.9% of HBeAg-negative patients.57,58 Telbivudine monotherapy results in genotypic mutations with virologic rebound in 21.6% of HBeAg-positive and 8.6% of HBeAg-negative patients within 2 years.59 Tenofovir and clevudine have lower incidence of resistance60,61 and entecavir has the lowest resistance rate (<1%).62 Tenofovir is effective in those who have developed resistance to lamivudine.63 In those with adefovir resistance, combination therapy with tenofovir and emtricitabine is potently more effective than tenofovir monotherapy.64,65 The role of combination therapy in treatment-naive individuals is being investigated. Adefovir in combination with lamivudine or emtricitabine has been shown to be more effective than monotherapy with lamivudine or adefovir.66,67
Pretreatment genotypic resistance testing in treatment-naïve persons is not routinely recommended at this time but may become important in the future to help determine appropriate treatment options.
Pregnancy Lamivudine, entecavir, and adefovir are category C drugs, but the larger experience with lamivudine has made it the agent of choice for HBV treatment in pregnancy and has been shown to decrease vertical transmission.68 Adefovir is avoided because it is embryotoxic and teratogenic in mice, at doses that attain serum levels 38 times that in humans, although it is safe at lower doses.69 If disease is mild, treatment may be delayed until after pregnancy. Regardless of treatment during pregnancy, perinatal immunoprophylaxis is crucial to minimize the risk of HBV-related disease in the neonate.
HIV/HBV coinfection Prevalence of coinfection is predicted to be high in the incarcerated population. In the USA, about 10% of HIV-positive persons are coinfected with HBV, and liver-related mortality in these patients is 17 times that for HBV-monoinfected patients.70 Coinfected persons have higher and prolonged HBV viremia and HBeAg seropositivity, with relatively lower ALT levels.71 Tenofovir, with emtricitabine or lamivudine, is a frequent component of antiretroviral regimens when both infections need treatment. Current treatment guidelines for HIV recommend that all HIV-infected individuals who need treatment for HBV infection should be started on a fully suppressive regimen for both infections, regardless of their CD4 counts or HIV viral loads.72 In case HIV treatment is not an option or is refused by the patient, HBV infection can be treated by using pegylated interferon-2α, which has no activity against HIV. Adefovir is another option for such individuals because of its lack of activity against HIV at a dose of 10 mg, which is used for treatment of HBV. Entecavir can induce M184V mutation in HIV when used as single antiviral in coinfected patients and is therefore avoided for HBV monotherapy in the coinfected.73 Telbivudine has not been shown to target HIV but is not preferred for HBV treatment in coinfected patients.45 Special caution is required in treatment of coinfected individuals with antivirals effective against both HIV and HBV. If changes in HIV genotypic resistance pattern warrant modification in the antiretroviral therapy, care should be taken not to discontinue drugs that are effective against HBV without substituting another agent with anti-HBV activity, unless the patient has achieved HBeAg seroconversion and adequate consolidation treatment. Sudden discontinuation of anti-HBV agent in patients who have not yet seroconverted can result in acute exacerbation of hepatitis.
HBV/HCV coinfection HBV/HCV coinfection causes accelerated progression of hepatic fibrosis and higher incidence of HCC.74 Most HBV/HCV coinfected patients have higher HCV RNA levels with predominance of that infection and lower HBV DNA levels with absence of HBeAg. Treatment should be initially directed at the virus that is more clinically and virologically dominant, with addition of therapy for the other virus if required. Peginterferon/ribavirin is the recommended regimen when both HCV and HBV are codominant.46 Suboptimal HBV response or breakthrough HBV viremia warrants addition of entecavir or adefovir.75
Cirrhosis These patients usually qualify for treatment regardless of the viral load and ALT levels. Combination therapy is preferred, with the agents of choice being adefovir or entecavir in combination with lamivudine. Those with decompensated cirrhosis should be referred for liver transplant as well. Current guidelines suggest that all individuals with HBsAg seropositivity and cirrhosis, regardless of their HBV viremia, should be screened for HCC by checking serum alpha fetoprotein (AFP) and liver ultrasound examinations every 6–12 months.76 Special groups of HBsAg-positive individuals recommended for HCC screening, even in the absence of cirrhosis, are Asians, HIV- or HCV-coinfected individuals, Africans over age 20, those with family history of HCC, and those with very high-level HBV viremia and ongoing hepatic inflammatory activity.76
Management of chronic medical diseases, including chronic hepatitis B and its sequelae, should be bridged over to community healthcare settings after discharge from correctional facilities. In the setting of HIV infection, lack of continuity of care results in loss of viral control, presumably associated with lack of access to antiviral medications or relapse to drug use.77 Timely initiation of discharge planning ensures continuity of care without any interruption and should include referral to medical care for continued access to discharge medications and immunizations, transitional housing, referrals to risk-reduction programs, and social services required to continue behavioral therapy. In addition, coordination and case management of long-term specialized care should be arranged for patients with disabling conditions, e.g. cirrhosis or HCC. Health education is of crucial significance for persons with blood-borne viral infections like HBV. These individuals should be educated about the risk factors for transmission of HBV, needle exchange programs, condom use, and avoidance of sharing toothbrushes, razors, etc. Vaccination of contacts should be arranged before patient discharge.
Correctional settings, with their structured environment and managed care approach, are ideal settings to screen, evaluate, and provide treatment and promote risk reduction interventions that will contribute to society’s improved public health. The rationale for testing for HBV infection is multifold. First, correctional institutions have high prevalence of HBV infection, which can be effectively treated with newer therapies.47 Second, undetected HBV has been associated with several outbreaks of acute HBV infection within correctional facilities that can be potentially avoided if HBV is detected upon entry.16 Third, given the high rates of recidivism in this population, they impose a high risk of transmission of blood-borne pathogens, including HBV, after release to the community. Fourth, individuals who learn that they are infected with a chronic infection tend to reduce their risk behaviors by more than 50%, as has been shown for intravenous drug users with hepatitis C.78 Fifth, a large percentage of prisoners are not immune to HBV and therefore eligible for vaccination consistent with existing public health guidelines.35 Sixth, vaccination of prisoners has been demonstrated to be a cost-effective strategy, with savings of US$ 2.13 for each US$ 1 invested in vaccinating inmates.79
Cost–benefit has been demonstrated not only in the prevention by vaccination but also in diagnosis and treatment of the hepatic disease imposed by HBV infection. Management of chronic HBV disease can result in person-life-years saved, quality-of-life-improvement, as well as economic benefit. Treatment with lamivudine has been shown to be extremely cost-effective, although current cumulative evidence suggests high risk of resistance and low anticipation for virological cure with lamivudine monotherapy and other agents are therefore preferred.80 Cost–benefit analysis on newer anti-HBV agents can be anticipated once investigations of prolonged use in longitudinal studies have been completed. The direct medical costs alone incurred by HBV infection demand an escalating dollar amount investment with advancing stages of disease. Cost–benefit analyses have determined that diagnosis and treatment of chronic hepatitis B is far more beneficial than managing late sequelae of untreated HBV infection.81 The annual healthcare cost of medical care for compensated cirrhosis increases more than 50-fold once hepatic decompensation occurs. Similarly, economic burden multiplies with diagnosis and management of HCC. Hepatic transplantation and post-transplant management impose the highest cost on the overall management of chronic hepatitis B.81 From the societal perspective, taking into account the direct nonmedical costs and indirect costs (e.g., decreased productivity, increased dependence on ancillary support, increased mortality) would altogether increase the adverse impact several fold more. The cost-effectiveness of early diagnosis and treatment per quality adjusted life year of HBV infection is especially relevant in managed care setting with limited budgets, like correctional facilities, especially for HBV-infected individuals who are incarcerated for several years. Public health importance of diagnosis, vaccination, and treatment considerations cannot be overemphasized, however, even for inmates incarcerated for a few years, given the high-risk behavior in this population and potential for transmission to the community after release from correctional facilities.
The authors would like to acknowledge funding from the Bristol-Myers Squibb Virology Research Fellowship (SG) and the National Institute on Drug Abuse (FLA) (K24-DA017072).