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Opioid use disorder and Chronic Hepatitis B
Introduction
Chronic hepatitis B virus (HBV) infection affects over 240 million individuals worldwide [ ]. Detection of the disease is dependent on active surveillance and testing by healthcare providers. Due to the high risk of transmission, the Center for Disease Control (CDC) recommends HBV screening in all individuals with opioid use disorders [ ]. Prompt identification of chronic infection and vaccination of susceptible persons at initial point of contact with the healthcare system is a priority. HBV diagnosis and prevention strategies should be coupled with effective harm reduction programs [ ]. Safe and well-tolerated oral antiviral therapy is available and is highly efficacious at suppressing viral replication and ameliorating long-term complications; however, there is at present no cure [ ]. Successful navigation of chronically infected individuals through the HBV care cascade ( Fig. 7.1 ) is critical to reduce HBV-related morbidity and mortality.
Natural history of hepatitis B virus infection
A heterogeneous disease, chronic HBV infection can manifest in many ways, from long-term inactive disease with little impact on life expectancy to severe acute hepatitis that leads to liver failure and death in the absence of liver transplantation. Risk of chronic HBV infection following exposure differs by age. Spontaneous resolution of hepatitis B after exposure is high among healthy adults but lower in adults who are immunocompromised.
The course of chronic hepatitis B is characterized by variable periods of high viral replication and active hepatitis (liver inflammation and injury) and more quiescent periods with low viral replication and inactive liver disease ( Fig. 7.2 ). The initial immune-tolerant phase (high viral replication, low activity) is typically absent or very short when infected in adulthood versus lasting decades in those infected as neonates or youngsters. Progression through the different phases of infection is not linear and all adults do not experience all phases during their lifetime. Roughly 30% of individuals with chronic HBV infection have an active disease phenotype marked by fluctuating periods of viral activity and subsequent hepatic inflammation (elevated alanine aminotransferase [ALT]) and intervening periods of viral quiescence [ ]. Over time, usually on the order of decades, the repetitive injury to the liver leads to the formation of liver fibrosis and ultimately cirrhosis in about 15%–25%. On the other hand, about 20%–30% of chronically infected individuals are inactive carriers, with low HBV DNA and normal hepatic enzyme levels, and possess a much more benign course of disease with minimal risk of cirrhosis over their lifetime unless coexisting liver diseases are present. Risk of HBV-related complications of cirrhosis and hepatocellular carcinoma (HCC) positively correlates with the level of HBV viremia.
Once chronic infection is established, spontaneous resolution is highly infrequent at all ages, with hepatitis B surface antigen (HBsAg) loss occurring at a rate of ∼1% per year [ ]. Furthermore, unlike other hepatotropic viruses, HBV integrates its DNA into hepatocytes and can be directly carcinogenic, leading to the development of liver cancer in the absence of fibrosis. Screening for liver cancer, therefore, is a critical aspect of clinical management in specific subpopulations of chronically infected individuals. Thus the vast majority of persons with chronic hepatitis B will require management of their infection over their lifetime, with the need for regular monitoring to determine indications for and duration of therapy. These considerations present unique challenges in the care of HBV-infected individuals with opioid use disorders.
Hepatitis B virus infection epidemiology, with focus on persons who inject drugs
Globally there are an estimated 15.6 million persons who inject drugs (PWID) in the adult population, [ ]. Substantial regional variation exists with respect to global HBV prevalence among PWID, reflecting the HBV endemicity of the region ( Fig. 7.3 ). While overall approximately 9.1% of PWID are HBsAg positive, the proportion is highest (20%) in East and Southeast Asia and lowest in Latin America and Western Europe (2.8% and 3.2%, respectively). The estimated HBV prevalence among PWID in North America is intermediate at about 5% [ ].
Injection drug use (IDU) accounts for the majority of HBV infections among those born in the United States. Unlike hepatitis C virus (HCV), prevention of HBV infection is achievable through widespread availability of a highly effective HBV vaccine. However, those born or infected before the introduction of universal birth-dose vaccination in the United States in 1991 remain at risk for acquisition of HBV and subsequent complications [ ]. In fact, the rise of opioid use disorders has been an important vector for the ongoing spread of HBV. In the past decade, acute HBV outbreaks among the IDU population have been reported in the Appalachian states and have signified a shift in the incident disease burden from urban to nonurban communities [ ]. Among those with opioid use disorders, transmission most commonly occurs through sharing needles, with sexual transmission being a secondary risk factor, which can be related to unsafe behaviors such as the exchange of sex for drugs [ , ]. In addition, incarceration occurs at higher rates among opioid users and is an established risk factor for HBV acquisition [ ]. Coinfection with human immunodeficiency virus (HIV), HCV, and hepatitis delta virus (HDV) is also more frequent among opioid users because of the shared routes of transmission, and these coinfections increase the risk of progression to end-stage liver disease [ , ].
Acute hepatitis B
Acute HBV infection may be accompanied by nonspecific symptoms such as fatigue, myalgias, nausea, and uncommonly jaundice, while symptoms are typically absent in those with chronic infection. Although usually self-limited, acute HBV infection can have severe consequences. Acute or fulminant liver failure due to HBV, defined as coagulopathy and encephalopathy within 8 weeks of symptom onset, occurs in 0.1%–0.5% of acute cases and spontaneous recovery without liver transplantation is infrequent even with prompt administration of antiviral therapy [ ]. Factors associated with a higher likelihood of acute liver failure among acutely infected PWID include concomitant alcohol use, methamphetamine use, HBV genotype D, and certain HBV mutations [ ].
Epidemiologic data on acute HBV incidence in opioid use disorders are sparse and lacks disaggregation by drug type. Outbreaks are commonly related to sharing of injection equipment including filters and water used to prepare/rinse syringes [ ]. An enhanced population-based surveillance strategy employed by six states (Colorado, Connecticut, Minnesota, Oregon, Tennessee, and New York) identified 2220 acute HBV cases between 2006 and 2011 with an average annual incidence rate of 0.86 per 100,000 persons [ ]. There was a decline in cases over time in all sites except Tennessee where the incidence peaked at 2.26 per 100,000 persons in 2011. The majority of cases were US-born, white, male, and aged 30–49 years (mean, 44 years). IDU, particularly of heroin, is the main driver for acute HBV infection in US regions with increasing incidence [ ]. Between 2006 and 2013, over 3000 cases of acute HBV infection were reported to CDC from the Appalachian states of Kentucky, Tennessee, and West Virginia alone, representing an increase of 113% in these three states. Over this period, the proportion of cases increased among those of white race, aged 30–39 years, and in nonurban counties (defined as population under 50,000). Report of IDU as a risk factor for HBV transmission increased as well (53% between 2006 and 2009 vs. 75% between 2010 and 2013), mirroring a rise in admissions for prescription opioid and heroin use disorders among young adults in these three states [ ]. The escalating incidence of acute HBV in the 30- to 49-year age group may reflect susceptibility due to a lack of inclusion in routine or catch-up HBV vaccination and a growing engagement in risky behaviors. Outbreaks are reported in other states, with Massachusetts reporting a 78% increase in acute HBV cases in 2017 and North Carolina seeing a 56% increase between 2014 and 2016 [ ], highlighting the need for broader vaccination efforts.
Natural history studies reveal that ∼90% of adults with acute HBV infection will clear HBsAg within 3–6 months, but delayed clearance of up to 2 years has also been described [ ]. In a prospective study of acute hepatitis from Europe (most reported sex as a risk factor), the median time to HBsAg clearance was 67 days (interquartile range [IQR], 32–132 days) and median time to hepatitis B surface antibody (anti-HBs) >10 IU/L was 109 days (IQR, 49–169.5 days) [ ]. In another study from Japan, HBV genotype A was found to be associated with delayed clearance of HBsAg (mean, 6.7 vs. 3.4 months), with 23% clearing HBsAg 6 months after the onset of acute hepatitis [ ]. By definition, chronic HBV infection means the presence of HBsAg for 6 months or more, but in the case of documented acute HBV infection, a longer period of follow-up may be needed to establish chronicity with certainty.
Resolved and occult hepatitis B
In the United States, approximately 3.9% of the population, an estimated 10.8 million individuals, has evidence of resolved HBV infection [ ]. Resolved HBV infection is very common in PWID exposed in adulthood. This reflects the high rate (>95%) of spontaneous clearance of HBV infection after acute infection among healthy adults. Risk of HBV exposure increases with the length of IDU. Therefore resolved HBV infection can be found in as high as 95% of those with greater than 30 years of use [ ]. Although resolved infection is generally regarded as benign, the presence of positive hepatitis B core antibody (anti-HBc) has been associated with 1.3-fold increased all-cause mortality in the United States, which may be attributable to coexisting high-risk behaviors rather than liver-related complications [ ]. However, reactivation of HBV infection (reversion to HBsAg positivity or reappearance of HBV DNA) in the setting of immunosuppression is an important risk in those with resolved hepatitis B. The risk not only is highest (>10%) with the use of anti-CD20 therapy (i.e., rituximab, ocrelizumab) and hematopoietic stem cell transplantation but also exists with exposure to cytotoxic chemotherapy, biologics, and high-dose corticosteroid therapy (1%–10%) [ ].
Occult HBV infection is defined as absent serum HBsAg, but presence of serum anti-HBc and detectable HBV DNA, albeit in very low concentrations. Theories for lack of circulating HBsAg include gene mutations that lead to HBsAg nondetectability and, more likely, robust immune control of virus leading to low HBV replication. High prevalence of this form of HBV infection has been reported among PWID, although prevalence measures are dependent on the sensitivity (lower limit of detection [LLD]) of the assay used. Among 188 HCV-positive PWID in Baltimore, Maryland, HBV DNA was detected in 45% using an enhanced PCR assay (LLD 15 copies/mL) compared with 0% when using an older COBAS PCR assay (LLD 200 copies/mL) [ ]. In another study from Taiwan, 41% of 301 HBsAg-negative PWID had positive results for serum HBV DNA (mean, 4.0 log copies/mL) [ ]. No mutations were found in 20 randomly selected samples. In both studies, occult infection was associated with older age, likely a reflection of duration of IDU and cumulative HBV exposure. While treatment is not indicated, occult infection has been linked to infrequent events of HBV transmission, fibrosis progression (particularly with HCV coinfection), HCC, and reactivation [ ].
Chronic hepatitis B
Current US estimates of HBV-infected individuals range from 0.8 to 2.2 million, many of whom are immigrants from endemic regions of Asia and sub-Saharan Africa [ ]. The seroprevalence of chronic HBV infection (positive HBsAg) has been relatively stable over the past two decades among US adults at 0.3%, based on the National Health and Nutrition Examination Survey (NHANES), although likely an underestimate because of the exclusion of military, incarcerated, and homeless population from sampling [ ]. Population-based estimates of HBV prevalence among self-reported PWID in NHANES are not available and other estimates of HBsAg seroprevalence among PWID have ranged from 3.5% to 20%, attributable to the study design (i.e., convenience sampling, recruitment site) and cohort differences [ ]. The higher prevalence of resolved versus chronic infection reflects the considerable burden of HBV exposure coupled with a high likelihood of clearance.
Data suggest that the trend in HBV exposure over time among PWID has largely declined. The proportion of anti-HBc-positive cases in cross-sectional sampling of IDU individuals in the Urban Health Study in San Francisco decreased from 68% in 1987 to 45% between 1998 and 2000 [ ]. Increased uptake of HBV vaccination is one explanation, as only 1% had serologic evidence of vaccination in the early period compared with 12% in the later period. Similarly, in a cross-sectional sampling of PWID residing in Seattle, anti-HBc prevalence declined from 43% to 15% between 1994 and 2004, with coexisting increases seen in self-reported needle-exchange use, condom use, and vaccination uptake [ ].
HBV-related mortality
About 1800 individuals die from the sequelae of chronic HBV infection yearly in the United States, including HCC and complications of cirrhosis [ ]. Mortality rates are much higher among those with opioid use disorders and IDU than the general population; most commonly early deaths are from drug overdose, suicide, traumatic injuries, and complications of HIV [ ]. The risk of liver-related mortality is estimated to be 17-fold higher among PWID as compared with the general population. Viral hepatitis accounts for three-quarters of those who die from liver disease, with chronic alcohol use contributing in up to 40% [ ]. Historically, the impact of HBV infection on life expectancy among IDU individuals was much less than that of chronic HCV infection [ ]. But the long latency of viral hepatitis means liver disease has emerged as a major contributor to mortality only as opiate-dependent populations have aged, particularly as life expectancy with HIV infection has lengthened with improved therapies. In a large Australian cohort of PWID, liver disease was the underlying cause of or contributed to 17% of deaths over 30 years; there was a clear uptrend over time, with 0 deaths per 1000 person-years between 1980 and 1984 to 5 deaths per 1000 person-years between 2005 and 2006, overtaking death rates from overdose [ ] ( Fig. 7.4 ).
Hepatitis B and other coinfections in persons who inject drugs
Coinfection with HIV, HCV, and/or HDV is frequently encountered among those with opioid use disorders because of the shared means of transmission. Age at first injection, incarceration, men who have sex with men (MSM), and greater number of lifetime partners have all been identified as risk factors for coinfection [ , ]. The interplay of viral dynamics in those with coinfection can have significant bearing on clinical outcomes, most notably the risk of cirrhosis, HCC, and liver-related mortality.
Human immunodeficiency virus
HBV screening is recommended in all HIV-infected persons, and all PWID and MSM who are HBsAg-positive should be tested for HIV [ ]. Among HIV-infected cohorts, rates of coinfection with HBV can be as high as 20% in endemic regions compared with 5%–8% in nonendemic regions, related to the age of exposure and likelihood of chronicity [ , ]. In nonendemic regions, HBV infection may precede HIV infection because of the more efficient transmission of HBV. MSM are a much stronger determinant of HBV infection risk than IDU among HIV-infected adults in nonendemic regions [ ]. In comparison, IDU accounts for most cases of HCV/HIV coinfection. Concurrent HIV infection influences the natural history of HBV infection: those with lower CD4 counts are more likely to develop chronic infection after exposure, experience HBV reactivation, and develop cirrhosis and HCC [ ]. Conversely, HBV infection appears to have little impact on HIV natural history, with no differences seen in progression to AIDS and response to antiretroviral therapy between HIV monoinfected and HIV/HBV coinfected persons [ ]. Among HIV-infected PWID, HIV care models provide an ideal opportunity to integrate HBV testing, vaccination, and treatment.
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