New Horizons in Hepatitis B and C in the Older Adult

Linda Kemp; Kathleen E. Clare; Paul N. Brennan; John F. Dillon

Disclosures

Age Ageing. 2019;48(1):32-37. 

Hepatitis C (HCV) and hepatitis B (HBV), are blood-borne viruses that can cause acute hepatitis; but are clinically relevant because chronic infection is associated with development of cirrhosis and hepatocellular carcinoma. Both these viruses are becoming more common in the older population, due to the ageing of generations exposed to the risk factors associated with infection; intravenous drug use, multiple sexual partners and men who have sex with men. This review will cover the natural history and epidemiology of these infections as well as the revolution in drug therapy that now allows cure of HCV infection and complete control of HBV infection.

According to the World Health Organization (WHO) Global Hepatitis report in 2017, approximately 257 million individuals have chronic HBV infection. Additionally, there are 71 million persons with chronic HCV seropositivity.[1] Untreated; HBV and HCV may sequentially lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma. These complications account for 96% of deaths relating to viral hepatitis.[1] Within this review, we will focus specifically on presentation, treatments and some of the associated morbidity within an ageing populace.

Hepatitis B

The virus was identified by the discovery of a new antigen termed Australian antigen (AuAg, now known as surface antigen).[2] Epidemiological studies estimate that one-third of the world's population has evidence of past or present infection.[3]

HBV belongs to the hepadnavirus family. It is a partially double stranded viral DNA capable of reverse transcriptase.[4] The complex viron has a double stranded-DNA, nucleocapsid (HBcAg) and the outer surface of the viron, the HBV surface antigen (HBsAg). Another nucleocapsid antigen is HBV e antigen (HBeAg).[5] It is transmitted when blood, semen or another contaminated bodily fluid from a person infected comes into contact with mucus membranes or an open wound of someone who is virus naive. Transmission may be though sharing of needles, syringes or other drug injecting paraphernalia, via sexual contact[6] or by vertical transmission (from mother to child) at birth.[7]

The natural history of the disease can vary from acute infection, inactive carrier state to progressive chronic HBV even leading to cirrhosis and potentially hepatocellular carcinoma.

HBV is a major global health problem. The prevalence varies and is an estimated 1.6% in the WHO European Region and 0.7% in the WHO Region of the Americas.[8] The UK falls into the lowest category of HBV prevalence, as determined by the WHO (0.1–0.5% of the population).[9] Although acute HBV infection rates have fallen rapidly, the data from the Health Protection Agency indicated the frequency of chronic infection is increasing. With increased emigration patterns there is an increased prevalence in previously low prevalence countries. In North America and Europe (including the UK) the main risk factors are birth in an endemic country, intravenous drug use and men who have sex with men. All of these risk populations are increasing in age, the teenagers of the 'swinging 60's' and the citizens from the decades of mass migration are now pensioners. Though these people are poorly representative of the elderly population as a whole.[5] There are scattered reports of HBV outbreaks in nursing home residents in the literature; however, these date from the 1970s.[10]

Clinical Manifestations

Acute HBV in older adults is usually mild and self-limiting. Infected elderly individuals often develop a subclinical hepatitis with a low rate of HBV clearance.[11] The pattern of liver function derangement can be cholestatic in nature; which can lead to the performance of unnecessary tests and be misleading as extrahepatic diagnosis such as pancreatic tumours or gall stones are considered first. Therefore, in every older patient presenting with elevated liver enzymes, it is suggested serological tests for hepatitis should be determined before proceeding to further investigation.[12] The course of chronic HBV is influenced by a multitude of variables including age.[13] In infants progression to chronic HBV has been reported in >90% of those infected, 25–50% of children aged 1–5 years old and progression from acute to chronic HBV occurs in less than 5% of young adults, but is observed more frequently in the elderly.[13] In Japan an outbreak in a nursing home lead to almost 60% of the infected becoming HbsAg carriers.[12] There are however some conflicting reports with regard to seroclearance with more than one study suggesting that age >60 years has been shown to be an independent predictor for HbsAg clearance, but this has principally been demonstrated in Asian populations.[14,15]

The virus stages of chronic HBV infection are classified by European Association for the Study of the Liver (EASL),[3] Table 1. The five phases are presented as a linear progression but it is important to note that patients can move back and forth between the phases.

  • Phase 1—Highly contagious; most commonly seen in children and young adults.

  • Phase 2—Most dangerous phase of chronic HBV infection, with patients progressing to cirrhosis and liver failure. This is the disease state targeted by current treatments, with the aim of suppressing viral replication.

  • Phase 3—This phase can reactivate to immune reactive, especially with inter-current illness, immunosuppressive therapy and some of the new biological agents.

  • Phase 4—Occurs in the presence of a HBV mutant virus that is not suppressed or only partially suppressed by the seroconversion from HBeAg to anti HBe-antibodies. This may be apparent immediately on leaving the immune-reactive phase or may become apparent after many years or decades of the inactive carrier state

  • Phase 5—This phase is also known as 'occult HBV infection'. Key to understanding this phase is the recognition that these patients had early phase of chronic infection and are different to the resolved/cured acute infection, despite the fact they have the same immunological profile. The true occults still have cccDNA in their livers, which can lead to re-activation of infection.

Vaccinations

Vaccination against HBV is recommended for children in many countries. In 2017, the UK vaccination programme was updated to include this. Vaccination for adults at increased risk of infection is also recommended.[16] Studies into the response of elderly patients to the HBV vaccination have found, antibody response to primary vaccination was delayed.[17]

Treatments

Treatments of chronic HBV have improved. Nucleoside analogues (NAs), now form the backbone of the armamentarium against chronic HBV, with Interferon alpha still making a contribution. The aim of treatment is to suppress the level of viral replication, as this is strongly associated with cirrhosis and hepatocellular carcinoma. This can be achieved immunologically or pharmacologically. Interferon therapy stimulates an immunological response that can lead to virological cure in up to 30% of cases, but with a formidable side-effect profile, success rates are lower in older patients. Pharmacological therapy is with NAs that suppress viral replication by direct interference in replication, these are highly effective, achieving complete suppression in most patients. However, they have to be taken long-term, as the suppression last only as long as the half-life of the drug. Overall, NAs have a reasonable side-effect profile and require infrequent monitoring. They are better tolerated and are the preferred treatment for those with significant fibrosis, cirrhosis or undergoing transplant. The need for treatment is determined by overall evidence of viral activity, seroconversion of Hepatitis e-Ag, evidence of necroinflammation and presence or absence of established liver disease, and should be co-ordinated by a specialist in infectious hepatitis.[18]

With regards to specific treatment strategies for elderly patients with chronic HBV; those with deteriorating renal function or osteoporosis, treatment with Tenofovir Alafenamide and Entacavir has been shown to have less systemic effects and is preferred. It is therefore suggested that patients at risk of deteriorating renal function especially those over 60 if already on Tenofovir Disoproxil are considered for a switch.[3]

Hepatitis C

The HCV is a blood-borne, hepatotropic RNA virus causing both acute and chronic infection. Acute HCV is rarely symptomatic; studies suggest spontaneous clearance rates of 26%.[19] Those who develop chronic HCV are also usually asymptomatic.[20] Chronic HCV is defined as the persistence of HCV RNA for at least 6 months after acute infection. This can cause significant intrahepatic damage before it is clinically recognized. Chronic HCV infection predisposes the individual to liver fibrosis, cirrhosis and hepatocellular carcinoma.[20] As well as this, 1–2% of chronically infected individuals will develop extrahepatic manifestations of the disease commonly cryoglobulinemia, membranoproliferative glomerulonephritis and vitiligo. Data also suggests an association between chronic HCV infection and the development of both Hodgkins and non-Hodgkins lymphoma.[21] HCV infection is diagnosed by blood showing a positive HCV antibody, which indicates current or previous infection (the antibody is not protective against further infection) and the detection of HCV RNA which indicates active infection requiring treatment. The combination of positive antibody and negative HCV RNA indicates spontaneous or treatment induced cure.

The rate of chronic HCV infection depends on many factors including gender, ethnicity, age at the time of infection and the presence of jaundice during the acute infection.[21] Of those with chronic HCV infection; it is estimated that 20% of individuals will go on to develop liver cirrhosis over 20 years. In these cirrhotic patients, there is a 25% risk of progressing to end-stage liver disease and 3–5% annual risk of developing hepatocellular carcinoma.[22,23] Centres for Disease Control and Prevention (CDC) have reported that worldwide, chronic HCV is the leading cause of liver transplant.[24]

The virus is transmitted by percutaneous exposure to infected blood. The leading mode of transmission since the 1970's has been injection drug use however other modalities of transmission include the reuse or inadequate sterilization of medical equipment, haemodialysis (typically unscreened blood products before 1992), healthcare work and military service.[13] Although uncommon; HCV can be transmitted through sexual activity, tattoos and vertically from mother to baby. Injection drug use remains the leading mode of transmission in the developed world whilst unsafe healthcare practice accounts for the majority of new infections in the East Mediterranean countries.[1] The WHO recommends HCV screening for individuals at increased risk of infection.[25]

HCV is endemic in most areas of the world. With an estimated global prevalence of over 71 million people (1% of the global population) and an annual incidence of between 3 and 4 million cases,[1] chronic HCV infection is one of the leading causes of chronic liver disease worldwide. There are considerable variations in the age and geographic prevalence of HCV infection and genotype; rates of disease differ across and within each country. According to statistics published by the WHO in 2017, the highest prevalence of HCV infection was found in the Eastern Mediterranean region (2.3%) followed by the European region (1.5%).[1] Data has shown that countries in the eastern and southern parts of Europe have a higher HCV prevalence than countries in the northern or western regions. The reported prevalence of HCV infection in the general population ranges from 0.1% in the Netherlands, Ireland and Belgium to 5.9% in Italy. Other counties with reasonably high rates of HCV include Romania (3.2%), Latvia (2.4%) and Greece (2.2%).[26]

In the USA, up to 80% of individuals infected with HCV were born during the 'baby boom' between 1946 and 1964.[27] Data suggests that individuals born during this period are five times more likely to have chronic HCV infection than other adults.[28] It is believed that the baby boomers became infected with HCV between the 1960's and 1980's. It is thought that in this generation, the introduction of new pathways of HCV transfer coupled with a lack of knowledge on the prevention of spreading blood-borne viruses has created a higher disease prevalence. To this day, the majority of people with chronic HCV infection are unaware of their condition. Even in those with a diagnosis, many do not know how or when they became infected.[28]

The US Census Bureau have projected that in 2030, the elderly population will comprise approximately 20% of the total US population.[29] Given the natural history of chronic HCV infection and its high prevalence amongst this cohort, it is no surprise that the incidence of hepatocellular carcinoma in the USA has tripled over the past decade.[30] The high seroprevalence amongst this age group coupled with the discovery of highly effective anti-viral therapy prompted the CDC to change HCV screening recommendations in the USA. In 2012, the CDC recommended a universal 'one-time testing', without ascertaining previous HCV risk, for individuals born between 1945 and 1965.[31] Despite this new recommendation, the 2015 National Health Interview survey revealed that only 13.8% had been tested for HCV. This slow uptake in screening is likely to be due to a lack of awareness amongst both patients and physicians to these new recommendations. Other influences may include the patient's unapparent symptoms and barriers to preventative medicine.[32]

It is estimated that <15% of patients with HCV know their status, it is important to have a low threshold to investigate patients presenting with signs and symptoms of liver failure.[33] In comparison with younger individuals, adults aged over 65 are more likely to present with complications of liver cirrhosis namely hepatic failure and hepatocellular carcinoma as an initial manifestation of HCV infection.[34] Features of decompensated liver cirrhosis include upper gastrointestinal bleeding secondary to oesophageal varices or portal hypertensive gastropathy, development of abdominal ascites, hepato-renal syndrome and hepatic encephalopathy.[21] The overall morbidity and mortality rates associated with the complications of acute and chronic liver disease are much higher in the elderly population. This is partly due to a higher prevalence of co-morbid conditions but also because physiological changes related to ageing make compensation and recovery difficult.[13] The treatment options available for advanced liver cirrhosis and hepatocellular carcinoma in elderly patients who do survive, are limited. Emphasis should be placed on screening the 'baby boomer' population as initiation of HCV eradication treatment may halt progression to advanced cirrhosis and its associated complications.

Treatments

Treatment of HCV infection has been revolutionized over the past decade. The new direct acting anti-viral regimens offer a sustained virological response (SVR) of 90–95% in patients with HCV-related liver cirrhosis including those with decompensated disease.[23] The efficacy and safety of treating HCV infection in elderly patients has previously been debated due to issues with compliance, co-morbid conditions and the side-effect profiles of the medications. However, the introduction of the newer, safer agents with lesser contraindications, provide highly effective therapeutic options for these patients who have previously been deemed unsuitable for treatment. Observational studies show the first generation protease inhibitor-based regimens had a similar efficacy to that of younger patients, albeit with more frequent adverse effects.[35] Therefore, the decision of whether to commence an elderly patient on HCV treatment should be guided by an assessment of liver-disease dependant and comorbidities dependant life expectancy and drug-drug interactions rather than their biological age. There is no vaccine for HCV presently.

Cirrhosis and Hepatocellular Carcinoma

In both chronic HBV and HCV both alcohol consumption and metabolic syndrome can accelerate disease progression. While the cause of liver disease is often multifactorial there are common pathological characteristics in cirrhosis. The cycles of viral assault on the liver and immunological response results in degeneration and necrosis of hepatocytes, replacement of liver parenchyma by fibrotic tissue and regenerative nodules, the loss of liver function and ultimately cirrhosis.[36] The cumulative effect of this at the time of viral cure or suppression determines the long prognosis and risk of development of the complications of cirrhosis and hepatocellular carcinoma.

Liver cirrhosis is the major risk factor for the development of hepatocellular carcinoma.[37] Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most common cause of cancer-related death.[38] Although hepatocellular carcinoma is more common in cirrhotic patients it can also develop in non-cirrhotic patients, this is well recognized in HBV patients, and there are now case reports of hepatocellular carcinoma in non-cirrhotic HCV patients. Hepatocellular carcinoma arises in a cirrhotic background in 90% of cases.[39] Recommendations by National Institute for Health and Care Excellence (NICE) are that patients with cirrhosis should undergo 6 monthly screening with ultrasound scan with or without alpha-fetoprotein. For those with cirrhosis and HBV surveillance should include alpha-fetoprotein testing. The aim of surveillance is to achieve a reduction in the overall mortality and should be cost effective.[40]

Male-to-female preponderance is greater than 2:1 in liver cancer, and ~83% of the estimated 782,000 new hepatocellular carcinoma cases in 2012 occurred in less developed regions. East- and South-Asia plus sub-Saharan Africa were the regions of highest incidence, Southern Europe and North America being of intermediate incidence, and Northern Europe and South Central Asia being of lowest incidence.[41] There have been enormous advances of treatments more recently. Treatments now include surgical resection or liver transplantation, TransArterial catheter ChemoEmbolisation (TACE), percutaneous radiofrequency ablation, percutaneous microwave coagulation therapy and molecular targeted therapy. Current guidelines for the management do not stratify for age.[42] Irrespective of these advances however, the overall mortality associated with non-transplanted hepatocellular carcinoma remains significant.

Conclusion

Presently both HBV and HCV infection are associated with intravenous drug use, non-sterile healthcare practice and unsafe sexual practice, however, the data has shown that one of the highest prevalence groups for infection is those aged over 65, particularly in the USA. It is therefore imperative that healthcare workers test elderly patients presenting with signs or symptoms of chronic or decompensated liver disease.

With the introduction of new and effective antivirals, the long-term sequelae of HCV induced liver disease in the elderly could become a problem of the past. Whilst therapies for HBV lag behind somewhat; there are increasing efforts to identify affected individuals early, prior to the development of chronic liver disease and its associated sequelae. Emphasis should also be toward effective vaccination programmes for HBV given the presently incurable nature of the virus.

It is imperative that we appreciate the burden of undiagnosed HBV and HCV that exists within elderly people; and ensure appropriate screening is undertaken at opportune times.

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