Objectives: To assess current knowledge of sexually transmitted viral hepatitis in relation to epidemiology, clinical presentation, management, and diagnosis with particular reference to resource-poor settings.
Method: A search of published literature identified through Medline from 1966 to October 2001, the Cochrane Library, and reference lists taken from each article obtained. Textword and MeSH searches for hepatitis A, B, C, D, E, G, delta, GB virus, GBV-C, and TT virus were linked to searches under the textword terms sex$, prevent$, and MeSH subheadings, microbiology, complications, drug therapy, therapy, diagnosis, epidemiology, transmission, and prevention and control.
Conclusions: In heterosexual relationships, hepatitis B is readily transmitted sexually and hepatitis C and D less so, with no evidence for sexual transmission of hepatitis A. Hepatitis types A–D are all transmissible sexually in male homosexual relationships under certain conditions. In resource-poor countries sexual transmission is generally only a significant route of transmission for hepatitis B.
- viral hepatitis
- sexual transmission
- tropical medicine
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Hepatitis B has been recognised as a sexually transmitted infection for over 25 years and more recent evidence supports sex as being one of the routes of transmission for hepatitis types A, C, and D. Although the viruses named hepatitis G, GB, and TT may also be sexually transmitted, current evidence suggests that these organisms do not cause disease and will not be discussed further. Similarly, hepatitis E will not be discussed further as there is no evidence for sexual transmission. The purpose of this article is to look at recent developments in our understanding of the sexually transmitted forms of viral hepatitis with reference to management in resource-poor settings.
This infection is usually transmitted by the faeco-oral route, including contaminated food and water, as well as by close personal contact.1,2 It is prevalent worldwide and the World Health Organization (WHO) recognises three levels of hepatitis A virus (HAV) endemicity (table 1). In countries with high endemicity, over 90% of adults and over 80% of older children may show evidence of past infection in seroprevalence studies.3 However, improving levels of sanitation in many countries in the last decade have led to a fall in childhood HAV infection with a concomitant rise in adults susceptible to symptomatic disease and outbreaks.4–6 Parenteral spread can also occur in injecting drug users, haemophiliacs using contaminated factor VIII, and other recipients of blood products.7–11
There are now numerous reports of HAV outbreaks among men who have sex with men (MSM). Infection correlates with visits to saunas and darkrooms, sex with anonymous partners, group sex, oro-anal and digital-rectal intercourse, and number of partners.12–15 Outbreaks are mainly confined to large cities including Melbourne, New York, London, Amsterdam, and Tokyo.12–18 However, the majority of MSM do not seem to be at increased risk, nor is there evidence for heterosexual spread of HAV.19–21 As HAV is largely a childhood infection in many countries, it should be no surprise that there is no evidence for sexual transmission as a significant route of infection in adults in resource-poor countries.
Hepatitis A has an incubation period of 2–6 weeks for clinically apparent infection. Disease usually starts with a flu-like prodromal illness lasting for up to 2 weeks, followed by icteric hepatitis which lasts for a few weeks and rarely longer than 3 months.2 However, disease manifestation is very much age related. For instance, only 5–20% of children under 5 years old will develop icteric disease, the rest having asymptomatic transient infection, and HAV related mortality is negligible in this age group.2 Therefore, icteric hepatitis A is a relatively uncommon disease in highly endemic countries with very high rates of childhood infection. Adults infected with HAV are more likely to develop icteric hepatitis (75–90%) although mortality remains generally very low (0.3%).2,22,23 The circumstance in which HAV infection has a significant mortality is when it occurs in older patients (over 40 years) or those with chronic liver disease, such as that due to hepatitis C, B, or alcohol.24–26
Diagnosis and management
Acute hepatitis A cannot be distinguished clinically from that due to types B, C, D, or E although in most resource-poor countries HAV is the leading cause of acute icteric hepatitis in children.2,3 Liver function abnormalities are similar for all types of acute viral hepatitis (table 2), but if resources allow, the diagnosis is confirmed by a serum antibody tests (table 3) using EIA.2,27,28
Most patients with acute icteric hepatitis will recover uneventfully on a regime of symptom control, rest, and adequate hydration and can usually be kept at home. In moderate/low endemicity countries there is a case for patient isolation, especially in patients with faecal incontinence, taking precautions against faeco-oral spread during the time of infectivity which is during the prodromal illness and for the first 2 weeks of jaundice.2,29 Normal human immunoglobulin may be given to non-immune close personal contacts, as may HAV vaccine.30,31 The vaccine may also be offered to those otherwise at risk such as non-immune travellers to endemic countries, MSM whose lifestyle puts them at risk, haemophiliacs, patients with chronic liver disease, or sewage workers.32 Universal vaccination of children in developing countries is now being considered although is currently prohibitively expensive.2
Epidemiology (table 4)
The majority of the world’s hepatitis B virus (HBV) carriers have caught the infection through vertical transmission at birth and horizontal infection of children.33,34 Other non-sexual routes of spread include horizontal transmission in institutions for patients with learning difficulties35 and parenteral exposure such as occurs among injecting drug users, or those infected nosocomially.36,37
HBV is very efficiently transmitted sexually during heterosexual and male homosexual contact.38–41 Heterosexual transmission occurs in many situations which includes sex with female sex workers in many resource-poor countries.42–45 Outside of prostitution, heterosexual transmission can still be important as shown by the 40% transmission rates to non-immune partners of patients with acute or chronic hepatitis B.34,35 The importance of heterosexual transmission varies from country to country. For instance in a Chinese seroprevalence study, most infection occurred in children under 5 years old but infection was also acquired by adults, some of whom are assumed to have acquired it sexually.34 In both India and Tanzania, countries with a medium prevalence of chronic HBV (1–5%), higher rates are found in STD clinic attendees and correlate with other STDs, especially syphilis.46,47 In fact, the Tanzanian study allowed an estimate of the proportion of hepatitis B that was sexually acquired in adults and was found to be 7.2% in men and 3.0% in women.47
Past studies of selected groups of homosexual men in the United States and Europe have found evidence of infection in 50% or more and HBsAg positive rates of up to 6%.39,40,48–55 Transmission of HBV in homosexual men correlates with duration of sexual activity, number of partners, oro-anal and genito-anal sexual contact.51,52 Despite the availability of an effective vaccine, HBV continues to be a significant problem in homosexual men in developed countries.53–55 There is relatively little published work on homosexual transmission of HBV in the tropics with the exception of parts of Latin America.56–58 In these countries there is evidence of very high rates of hepatitis B spread between homosexual men with indicators of present/past infection of over 40%.56–58
As with HAV, acute infection of children with HBV is largely asymptomatic59,60 and this situation accounts for the majority of HBV infections in resource-poor countries.33 In adulthood many infections are asymptomatic, but 20%–35% of infections are marked by acute icteric hepatitis which tends to be more severe than that due to HAV. However, in the immunocompromised, including those who are HIV positive, asymptomatic acute infection is common.60,61 For those with symptomatic disease, the incubation period is usually 6–12 weeks but can be as long as 6 months. HBV infection also causes fulminant hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. Approximately 1% of those with acute symptomatic infection will get fulminant hepatitis, marked by evidence of decompensated liver disease and leading to death in up to 50%.59 Numerically far bigger is the problem of chronic infection, cirrhosis, and liver cancer. Ninety per cent of infants, 50% of preschool children, and 10% of adults with HBV will become chronically infected—that is, for more than 6 months.33,59 Once chronic infection is established, this state may remain for decades and it is estimated that approximately 25% of chronically infected children will ultimately die of cirrhosis or liver cancer, usually from the fourth decade of life onwards and currently causing the death of about a million people annually.33
The majority of those with chronic infection have no symptoms until cirrhosis and decompensated liver disease develop in up to half of them when they experience abdominal ascites, jaundice, bleeding oesophageal varices and ultimately confusion, cachexia, and death. Both fulminant hepatitis and more rapidly progressive cirrhosis occur when chronic hepatitis B is complicated by hepatitis A, C, or D.62–64 About 10% of those with cirrhosis get liver cancer65 which presents with an enlarging liver, weight loss, and rapid progression to death.
Diagnosis and management
Acute icteric hepatitis B is clinically similar for all types of viral hepatitis. Similarly, cirrhosis and liver cancer due to HBV cannot be distinguished on clinical grounds from those due to hepatitis C although HBV is the most common cause in most resource-poor countries.33 A liver function test is available in many low resource healthcare settings and the pattern of abnormality for acute infection is similar for all types of viral hepatitis (table 2). Those with chronic hepatitis may have a normal liver function test apart from a mildly raised serum aminotransferase level (AST or ALT), although when cirrhosis or cancer develop, the LFT becomes progressively more abnormal as does the serum prothrombin time.66 HBV infection is confirmed by the presence of the serum surface antigen, a test which may be within the financial reach of many resource-poor settings, but to get more accurate assessment of the stage of infection more sophisticated and expensive assays for hepatitis B e antigen, and antibodies to the hepatitis B core, e and surface antigens needs to be done (table 3).66 The most sensitive test of all is the HBV DNA assay,66 which can be used to clarify issues if the antibody and antigen tests are not completely helpful (for example, in HBeAg negative replicative infection),67 although the expense of this assay limits its use to only the most technologically sophisticated of laboratories.
The management of acute hepatitis is the same as that for hepatitis A. Chronic, HBeAg positive, infection can be cured in up to 50% of patients with drugs such as interferon alfa, lamivudine, famciclovir, and adefovir,68–71 but the expense of these drugs has limited their use in resource-poor countries to a few healthcare settings.72 HIV co-infection with HBV also complicates management in as much as therapy for HBV is less effective except in those with a high CD4+ lymphocyte count.73,74 However, although the prognosis of liver disease in HIV/HBV co-infection may be worse,75 this has not been entirely confirmed. There may be some advantage in prescribing lamivudine as part of any antiretroviral regimen, if available, in HIV/HBV co-infected patients in as much as the progression of liver disease may be delayed.74 Once cirrhosis and liver cancer have developed, death is inevitable outside of those settings where liver transplantation and chemotherapy are available.33 By far the most effective population strategy is universal vaccination, as advocated by the WHO. In Taiwan, widespread HBV vaccination, aiming particularly at infants and children has led to a 80% fall in chronic HBV carriage in children with similar decreases in childhood liver cancer. It is hoped that the HBV carrier rate in Taiwan will be <0.1% by 2010.76 Similarly in China, the country with the largest number of HBV carriers, it is hoped that it will be virtually eradicated within a lifetime.77 Certainly vaccination and consistent condom use will prevent most cases of sexually transmitted hepatitis B if advised to those at risk.39,40,78
HEPATITIS D (DELTA VIRUS)
This RNA virus can only exist as a co-infection with hepatitis B but its geographic distribution is not uniformly identical to HBV (table 4). There are three main types of epidemiological pattern: endemic carriage (for example, Mediterranean basin, indigenous people in parts of South America), areas of mainly parenteral spread (for example, western Europe, North America) and areas with sudden epidemics (for example, in the Amazon basin, or central Africa).79–82 Rarely, vertical (mother to infant) spread may also occur.79
Several studies have shown sexual transmission of delta virus in both heterosexual couples and homosexual men and this route is significant both in endemic areas and in relation to injecting drug users in low prevalence countries.48,79,83,84
Delta virus (HDV) can be first acquired concurrently with acute HBV infection or as a superinfection of a chronic HBV carrier. In acutely co-infected patients the incubation period is 3–7 weeks and there may be two bouts of clinical hepatitis due to each virus.79 The acute infection is often quite severe and fulminant hepatitis is 10 times more likely than with other types of viral hepatitis with an 80% fatality rate.79 Chronic infection occurs in only 5% of such patients. Superinfection of HDV in a HBV carrier causes an acute, severe, icteric hepatitis which again is associated with a high rate of fulminant disease and also leads to chronic infection in 80%.79 Chronic infection leads to a high rate of subsequent cirrhosis (up to 70%) which is usually more rapid in onset (40% in 6 years) than with HBV and can occur as little as 2 years after infection.79,85 The rate of progression to liver cancer in cirrhotics with HDV is also trebled compared to HBV alone (adjusted odds ratio of 3.2, 5 year risk 10% v 2–4%).85
Diagnosis and management
Apart from the severity of infection, the only other clinically distinguishing feature is its propensity to cause acute hepatitis in known hepatitis B carriers (table 2).79 Laboratory diagnosis can be established by a serum anti-HDV test (table 3) although the utility of this test in resource-poor settings is doubtful except to investigate epidemics. Antigen and RNA tests also exist but require a relatively high level of technological expertise.86
Management is along the same lines as HBV except that to date there is no effective antiviral therapy. However, this infection is largely preventable through HBV vaccination, condom use, sterile medical equipment, and the avoidance of equipment sharing in injecting drug users.79
Epidemiology (table 4)
Parenteral transmission is the predominant route of transmission in most resource-poor countries.87–89 It is unclear how important vertical (mother to infant) transmission is in HIV negative women but, as with all other situations, HIV co-infection markedly increases the rate of hepatitis C virus (HCV) transmission to over 9% and may also lead to spread through breast milk.90 In developed countries the majority of carriers are injecting drug users, their partners, or those who have received untested blood or blood products
HCV can be sexually transmitted (unprotected vaginal sex) but at a relatively low rate, probably 0.5–2% per year of a relationship or 5% of all heterosexual relationships. Transmission rates are markedly higher if the source patient is also HIV positive.91–93 There is also evidence for homosexual spread.94 However, these data are from studies in Europe and the United States. Studies on sexual transmission in resource-poor countries are less certain. For instance, reports from Malawi, Jamaica, and Tanzania did not show evidence of significant sexual spread of HCV in the general population.95–97 Conversely, research in Thailand, Argentina, and Egypt does link HCV spread to heterosexual sex, particularly in relation to HIV infection.89,98,99 As with hepatitis A, this evidence therefore suggests that sexual transmission may occur in resource-poor countries but at a rate that is relatively minor compared with other routes of spread.
After an incubation period of up to 150 days, icteric hepatitis occurs in under 20% of acute infections, the rest being asymptomatic.87,100,101 Fulminant hepatitis is rare except for hepatitis A superinfection of chronic HCV disease.102 However, about 80% of patients develop chronic (>6 months) infection and spontaneous recovery is rare in such people.87,100,101 Symptoms of chronic infection are rare until cirrhosis intervenes which happens in about 20% after 20 years. Liver cancer also develops in up to 5% of carriers after 20–30 years. Progression to cirrhosis is more likely and more rapid if there is co-infection with HIV, HBV, or a high alcohol intake.87,100,101
Diagnosis and management
There is no way to distinguish acute icteric (table 2) and chronic HCV infection from other types of viral hepatitis on clinical grounds. Antibody tests are available (table 3) but expensive. Usually, an ELISA is used for screening, and the positive test confirmed by a RIBA because of the high rate of false positive tests by the ELISA method.103 It can take anything up to 9 months after exposure to HCV for the patient’s antibody test to become positive although most are positive within 3 months.87,103 For settings with advanced technological facilities a polymerase chain reaction (PCR) assay can be used to determine if an antibody positive patient is an HCV carrier, although over 90% are.103
There is no effective vaccine and so prevention is centred around non-reusable medical equipment, education, testing of donated blood, and safer sex including condoms.87 However, it is wise to vaccinate HCV carriers against hepatitis A and B to prevent the severe consequences of co-infection with these viruses.87,100,101,102 Approximately 50% of carriers can be cured using a treatment combination of pegylated interferon injections and ribavirin for 6–12 months, although this is very expensive and beyond the scope of most resource-poor countries.104
Series editor: David Lewis