HIV–HBV Coinfection — A Global Challenge
Athena P. Kourtis, M.D., Ph.D., M.P.H., Marc Bulterys, M.D., Ph.D., Dale J. Hu, M.D., M.P.H., and Denise J. Jamieson, M.D., M.P.H.
N Engl J Med 2012; 366:1749-1752May 10, 2012
Best viewed, with maps, at http://www.nejm.org/doi/full/10.1056/NEJMp1201796
Human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) exact a high toll worldwide. Both can lead to chronic disease, cancer, and death, and neither can be eradicated with the use of current therapies. Antiviral drug resistance often develops after patients have received treatment for some time and is usually followed by the loss of clinical benefit. Coinfection with the two viruses exacerbates the negative effects.
Worldwide, HBV is the leading cause of chronic liver disease and a leading cause of death, accounting for up to half of all cases of cirrhosis and hepatocellular carcinoma.1 An estimated 400 million people are infected with HBV,1 with the majority of cases occurring in regions of Asia and Africa where the virus is endemic. There, up to 70% of adults show serologic evidence of current or prior infection, and 8 to 15% have chronic HBV infection.1
These staggering infection rates largely reflect a failure of maternal and child health programs. The majority of HBV infections in settings where the virus is highly endemic occur through perinatal transmission (predominant in East and Southeast Asia) or in young children, transmitted through close household contact or through medical or traditional scarification procedures (predominant in Africa).1 Perinatal HBV infection is associated with a 90% risk of chronic hepatitis B, as compared with a risk of less than 5% among adults with intact immunity.1 The risk of perinatal transmission is lower in Africa than in Asia, a disparity that could be due to a lower prevalence of hepatitis B e antigen (HBeAg) and other differences in the pathogenic characteristics of circulating HBV genotypes.1
According to the Joint United Nations Program on HIV/AIDS (UNAIDS), about 33 million people are infected with HIV worldwide, and the majority of them live in Asia and Africa. Approximately 10% of the HIV-infected population has concurrent chronic hepatitis B,2 with coinfection more common in areas of high prevalence for both viruses. In countries where the viruses are highly endemic, the rate can be as high as 25%.2
In areas where HBV is less endemic (North America, Europe, and Australia), HBV and HIV are most often acquired during adolescence or adulthood through sexual transmission or injection-drug use. The prevalence of HIV–HBV coinfection in these regions is generally less than 10% of the HIV-infected population.2 However, up to half of injection-drug users infected with HIV are coinfected with HBV. Worldwide, there may be 3 to 6 million HIV-infected people living with chronic HBV (see maps Prevalence of HIV-1 and HBV Infection, According to Country.).
HIV–HBV coinfection increases the morbidity and mortality beyond those caused by either infection alone. People coinfected with HIV have higher levels of hepatitis B viremia, have progression to chronic hepatitis B that is approximately five times as fast as that among people infected with only HBV, and have a higher risk of cirrhosis and hepatocellular carcinoma.1 HIV immunosuppression can even cause the loss of hepatitis B surface antibodies and reactivation to chronic hepatitis B.1 As compared with healthy, uninfected persons, those infected with HIV — particularly the most immunocompromised — mount poorer antibody responses to HBV vaccination. Managing hepatitis B in HIV-coinfected patients is further complicated by the dual activity of several nucleoside analogues, the emergence of resistant HIV or HBV strains, the limitations of and decreased response to interferons, and the more rapid development of lamivudine-resistant HBV.2
Very few studies have addressed coinfection with HBV among HIV-infected pregnant women. Studies in Africa indicate that they are three times as likely as HIV-negative pregnant women to test positive for HBV DNA and twice as likely to test positive for HBeAg. Both higher HBV DNA levels and HBeAg expression are associated with an increased risk of an HIV-infected pregnant woman's transmitting HBV to her child.1
Vaccination of infants against hepatitis B is highly protective, reducing the risk of infection by more than 70% (the addition of hepatitis B immune globulin reduces the remaining risk by half. However, many countries with a high prevalence of HBV lack universal or timely vaccination coverage, and hepatitis B immune globulin is often unavailable or prohibitively expensive. In 2006, for example, the coverage rate for the vaccine dose at birth was only 36% in countries where the prevalence of chronic HBV infection exceeded 8%.
Even with appropriate vaccination, 5 to 15% of infants born to mothers who test positive for hepatitis B surface antigen (HBsAg) become infected. The proportion is much higher among infants whose mothers have high serum HBV DNA levels; transmission rates of 39% or higher have been noted.3 High HBV DNA levels are often seen in women with concurrent HIV infection, particularly in Southeast Asia, where HBV is highly endemic and perinatal transmission of HBV is already common.
Additional approaches are needed to protect children of infected mothers. For example, the use of antiviral therapy in pregnant women with high HBV loads has been examined in a few small studies and has shown promise in decreasing perinatal transmission3; this strategy appears to be cost-effective and should be explored further.4 Women coinfected with HIV would be good candidates for this preventive approach.
Even in areas with historically low rates of HBV, challenges exist. In the United States, the number of HBV-infected pregnant women is probably underestimated, with current methods relying on the expectation that certain ethnic groups are at high risk. In Europe, there is no consistent policy of testing women for HBV infection during pregnancy; some countries rely on assessment of “risk factors” alone. Immigration patterns in Europe and North America suggest that HBV prevalence will vary by region.
There are a number of unanswered questions about disease pathogenesis in coinfected persons and the management of HIV–HBV coinfection, especially in pregnant women. Pregnancy itself can trigger elevations of liver enzymes. The administration, during pregnancy, of antiretroviral prophylaxis containing one agent with anti-HBV activity may be associated with later development of HBV resistance. For pregnant women who, to prevent perinatal HIV transmission, take antiretroviral prophylaxis containing one or two agents with anti-HBV activity, the safety of stopping treatment after delivery is unknown. The administration of antiretrovirals without HBV activity in coinfected pregnant women may leave their infants unprotected against HBV. Finally, infection of the infant with HIV threatens the benefits of HBV immunization for perinatal prevention.
What will it take to address this crisis? First, we must acknowledge that HBV–HIV coinfection represents a major global public health threat. Because each virus affects the other's natural history and response to therapy, HIV–HBV coinfection requires dedicated research. A willingness to rapidly implement new scientific evidence is critical. Preventing transmission of both viruses to the next generation should be a priority for health policymakers.
Ideally, all pregnant women should receive early prenatal care with voluntary HIV and HBV testing to permit timely interventions aimed at preventing perinatal transmission.5 Use of antiretroviral agents with dual antiviral activity is a promising preventive approach — one limited, however, by a paucity of data on important agents (e.g., tenofovir) regarding safety during pregnancy, for both the fetus and the mother. As regimens including tenofovir become first-line therapy for many HIV-infected people (and are used as preexposure prophylaxis for the uninfected), determining the safety of these medications during pregnancy becomes a critical research need. Evaluating the HBV viral load in HIV-infected pregnant women should be an essential step of prenatal evaluation, so that the mother's health can be managed appropriately.
Continued improvements in the coverage and timeliness of HBV vaccination and the education of clinicians about its importance should be priorities everywhere. Making such improvements will require substantial advocacy and political and financial commitment. Now is the time to provide the best care we can for coinfected people and to protect a future generation of children from the largely hidden epidemic of HBV-related liver disease, which is being further fueled by the HIV epidemic.
The opinions expressed in this article are those of the authors and do not necessarily reflect the position of the Centers for Disease Control and Prevention.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
From the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion (A.P.K., D.J.J.), the Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (D.J.H.), and the Division of Global HIV/AIDS, Center for Global Health (M.B.), Centers for Disease Control and Prevention, Atlanta; and the CDC Global AIDS Program, Beijing, China (M.B.).
1Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis 2007;7:402-409
2 Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology 2009;49:Suppl:S138-S145
3 Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat 2009;16:94-103
4 Unal ER, Lazenby GB, Lintzenich AE, Simpson KN, Newman R, Goetzl L. Cost-effectiveness of maternal treatment to prevent perinatal hepatitis B virus transmission. Obstet Gynecol 2011;118:655-662
5 Kourtis AP, Bulterys M, Nesheim SL, Lee FK. Understanding the timing of HIV transmission from mother to infant. JAMA 2001;285:709-712
1Peter D. Burbelo, Joseph A. Kovacs, Jason Wagner, Ahmad Bayat, Craig S. Rhodes, Yvonne De Souza, John S. Greenspan, Michael J. Iadarola. (2012) The Cancer-Associated Virus Landscape in HIV Patients with Oral Hairy Leukoplakia, Kaposi's Sarcoma, and Non-Hodgkin Lymphoma. AIDS Research and Treatment 2012, 1-10
‘[A] global policy of universal HBV vaccination is ultimately the only way to eliminate HBV transmission and prevent serious HBV-related liver disease.’
Journal of Infectious Diseases,Volume 206, Issue 4,Pp. 464-465.
J Infect Dis. (2012) 206 (4): 464-465.
First published online: April 16, 2012
Ida Louise Heiberg and Birthe Hogh
+ Author Affiliations
Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
Correspondence: Ida Louise Heiberg, MD, Department of Pediatrics 460, Hvidovre Hospital, University of Copenhagen, Kettegård Allé 30, 2650 Hvidovre, Denmark (firstname.lastname@example.org).
Text below; see also related research article at http://jid.oxfordjournals.org/content/206/4/478.full
Hepatitis B virus (HBV) infection remains an important global health problem despite the availability of a safe and effective vaccine; >350 million people worldwide are chronically infected . Infection with HBV in adults most often results in self-limited, acute hepatitis that confers protective immunity and causes no further disease. In contrast, most children fail to clear the virus, resulting in chronic infection in 90% of children who are infected perinatally. Chronically infected children are generally asymptomatic but are at risk of developing liver cirrhosis and hepatocellular carcinoma [2, 3]. Since 1992, the World Health Organization has recommended global vaccination against HBV, and by the end of 2009, 177 countries had implemented a universal HBV immunization program for newborns, infants, and/or adolescents. Countries with a low level of HBV endemicity, such as Japan and many northern European countries, have adopted a strategy in which vaccination is offered to individuals at high risk of infection .
Spread of HBV occurs through contact with blood or other bodily fluids of an infected person. In countries with low endemicity, the spread of HBV is caused predominantly by sharing contaminated equipment during drug injections and through sexual contact.
In this issue of the Journal, Komatsu et al report their findings of high levels of HBV DNA in tear specimens from children with chronic HBV infection and show how inoculation with these specimens led to HBV infection in chimeric mice. Furthermore, they report high levels of HBV DNA in saliva, sweat, and urine samples from children with chronic HBV infection, results that are supported by several studies [5–8]. In countries where only high-risk groups are vaccinated, these findings are of clinical importance when assessing the real and the perceived risk of horizontal transmission of HBV. Children with chronic HBV are more prone than adults to be HBV e antigen positive and to have a high viral load. At the same time, children are more likely to have contact with each other's body fluids, such as saliva and tears, and therefore have a high risk of horizontal transmission. Horizontal transmission is especially important in children who are at a high risk of acquiring chronic, asymptomatic infection when exposed to HBV. That children often are asymptomatic after infection with HBV lets them enter the large pool of chronic carriers unnoticed.
The report by Komatsu et al provides further evidence of the risk of horizontal transmission, although the precise mechanisms of transmission are unknown. It may possibly be due to contact of nonintact skin or mucous membranes with tears, saliva, or blood-containing secretions. Transmission from sharing personal care items such as toothbrushes may also occur .
As Komatsu and colleagues state, physicians from countries with an HBV vaccination strategy targeting at-risk individuals are keen to know whether various body fluids are sources of HBV transmission; in addition, they are concerned whether these strategies are effective in preventing HBV infection. It is believed that the ideal HBV immunization strategy is to implement universal vaccination for children or adolescents . By this strategy, lower carrier rates of HBV surface antigen in children are seen within relatively few years , but it is important to state that several immunization strategies are needed in areas of low endemicity until universal vaccination has been in place for 20–40 years.
The issue of cost-effectiveness is important in countries where HBV has a low level of endemicity, but although the strategy focused on at-risk individuals might initially appear to be a cost-saving approach, the cost of the vaccine is only a small part of the overall cost of immunizing high-risk individuals. Implementation of the high-risk strategy is very resource intensive . Furthermore, people in high-risk groups, such as injection drug users, might have difficulties adhering to an immunization schedule. Increased frequencies of travel make the discussion highly relevant, since unvaccinated individuals are at risk of infection when traveling in settings where HBV is endemic. High rates of immigration also contribute to the importance of this subject, particularly when they involve people who move from countries of high endemicity to countries of low endemicity where universal vaccination has not been implemented. A targeted immunization program is needed for individuals who are at risk for HBV infection because of their occupation, lifestyle, or other factors (eg, close contact with chronically infected individuals). But such programs, when used alone, have never proven effective at reaching all targeted individuals, which suggests the need to revisit the use of targeted vaccination strategies in areas where the endemicity of HBV is low. On the basis of this knowledge, the Netherlands recently changed their strategy and decided to incorporate HBV vaccine in their national immunization program .
In spite of the low risk of transmission in countries where the endemicity of HBV is low, concern about the infectivity of children with chronic HBV infection is substantial for families in which a child is a chronic carrier of HBV. Chronic HBV infection is complex, and there is a need to ensure that those affected by chronic HBV infection are not stigmatized . HBV infection disproportionately affects people from low- and middle-income countries. In these countries, high rates of chronic HBV infection are related to high levels of mother-to-child and early childhood transmission, because of a lack of comprehensive immunization programs. Stigmatization and discrimination continue to be unfortunate responses to children with chronic HBV infection, especially in countries where universal vaccination has not been implemented .
HBV infection is a vaccine-preventable disease, but although global control is achievable, it has not yet been attained. HBV vaccine is the first effective vaccine against a major human cancer. Twenty years after the availability of HBV vaccine, we are still far from worldwide eradication of the disease. The World Health Organization recommends that HBV vaccine should be included in routine immunization schedules in all countries, and a global policy of universal HBV vaccination is ultimately the only way to eliminate HBV transmission and prevent serious HBV-related liver disease.
Presented by Ann M. Buchanan (United States).
Abstract below; also at http://pag.aids2012.org/abstracts.aspx?aid=18997
F.J. Muro1, S.P. Fiorillo2, C. Odhiambo1, C.K. Cunningham3, A. Buchanan1,3,4
1Kilimanjaro Christian Medical Centre, Moshi, United Republic of Tanzania, 2University of Colorado, Denver, Division of Infectious Diseases, Aurora, United States, 3Duke University Medical Center, Division of Infectious Diseases, Department of Pediatrics, Durham, United States, 4Duke Global Health Institute, Duke University, Durham, United Republic of Tanzania
Background: Data on HIV and hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection among children in Africa are scarce. We evaluated the seroprevalence of HBV and HCV among healthy HIV-uninfected children and HIV-infected children in the Kilimanjaro Region of northern Tanzania.
Methods: HBV and HCV markers were assessed on banked serum and plasma samples from HIV-negative children ages 1 month to 18 years and HIV-infected children on highly active antiretroviral therapy (HAART) a minimum of six months from 1 to 16 years of age. HBV markers included hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (HBcAb). Infection was defined as a single positive HBsAg or HBcAb result. HCV infection was assessed by anti-HCV ELISA. Validation studies were performed on all assays prior to use and all were FDA-approved.
Results: Samples from 560 children were available for testing. Of 394 HIV-negative children, 36 (9.1%) were HBV-infected, and of 161 HIV-infected children, 33 (20.5%) were HBV-infected. Children with HIV were 2.6 times more likely to be HBV positive (95% CI 1.53, 4.29) than children without HIV (p=0.0002). None of the 560 samples was positive for anti-HCV antibody.
Conclusions: HBV seroprevalence is high among children in the Kilimanjaro Region, with a significantly higher prevalence among HIV-infected children. Routine screening for HBV should be performed among HIV-infected children. Patients with co-infection require closer monitoring of liver transaminases due to hepatic toxicities associated with antiretroviral therapy, and must be provided with appropriate HAART which will target both viruses. Catch-up immunization with HBV vaccine should be considered for older HIV-infected children.