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Prevalence of Hepatitis B and C Virus Infections in Children Infected with HIV in USA & Developing World
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Clinical Infectious Diseases Sept 15, 2007;45:795-798
Sima Shelly Toussi,1 Jacobo Abadi,2 Michael Rosenberg,2 and Daniela Levanon2
1Department of Pediatrics, Children's Hospital at Montefiore, and 2Department of Pediatrics, Jacobi Medical Center, Bronx, New York
We evaluated the prevalence and transmission mode of hepatitis B and C in an inner-city, pediatric cohort of human immunodeficiency virus (HIV)-infected persons, as well as the demographic characteristics of the cohort. Hepatitis B or C was found in 13 (5.8%) of 228 children. This analysis suggests that chronic hepatitis is prevalent and should be routinely screened for in the pediatric HIV-infected population..... The HBV- and HCV-coinfected children were more likely to have mildly elevated transaminase levels....."the focus of our efforts must turn to the developing world-especially in Asia, where the burden of HIV infection and chronic viral hepatitis is greatest [17]. Unfortunately, access to the resources necessary to address these 2 intersecting epidemics is limited in the regions of the world where it is most needed. However, as the net of antiretroviral therapy gradually expands, it will be imperative to institute preventive strategies and to develop guidelines that can effectively manage chronic HBV or HCV infection in HIV-infected children and adolescents."
BACKGROUND
Because HIV-infected children in the United States are living longer, hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfections are important comorbidities to consider when making management decisions. However, the prevalence of HBV or HCV infection and its impact on HIV-infected children has been poorly characterized.
The Third National Health and Nutrition Examination Survey (NHANES III), which was conducted during 1988-1994, reported 0.2% prevalence of chronic HCV infection among children aged 6-11 years, whereas 1.8% of children aged 6-19 years have serologic markers of past or current HBV infection [1-3]. The current prevalence of chronic viral hepatitis among children is likely to be lower than these figures suggest, because of the introduction of universal screening of blood products for HCV antibodies in 1992 and the implementation of mandatory HBV screening of pregnant women and vaccination of exposed newborns in 1991.
The prevalence of chronic viral hepatitis in HIV-infected children is unknown. It would be expected to be higher than the prevalence in the general pediatric population, because all 3 viruses are acquired predominately by vertical transmission, and infants exposed to HBV or HCV are more likely to develop chronic infection. Perinatal acquisition of HCV increases 3-5-fold when mothers are coinfected with HIV and HCV, particularly if the mother's HCV load exceeds 1 million copies/mL [4-6], and >90% of newborns who are exposed to HBV and who do not receive postexposure prophylaxis develop chronic infection [12].
The epidemiology, natural history, and treatments for coinfected adults, in contrast to children, have been studied extensively. HIV-infected adult cohorts report a 30%-50% rate of coinfection with HCV and an 8% rate of coinfection with HBV [7, 8]. The higher prevalence among adults is a consequence of the common modes of transmission of these viruses: injection drug use and unprotected sex. Compared with patients who are infected with HIV alone, coinfected adults are more likely to develop chronic hepatitis, to have more severe liver disease, to experience HIV treatment failure, to have higher viral loads (for both viruses), and to develop antiretroviral-associated hepatotoxicity [7, 9]. A single pediatric multicenter study found that 1.5% of 525 HIV-infected children were coinfected with HCV [10]. Finally, the clinical impact of chronic viral hepatitis in HIV-infected children is unknown. In this report, we present the prevalence of HBV and HCV coinfection, demographic characteristics, and mode of transmission in a group of pediatric HBV-HIV- and HCV-HIV-coinfected patients, and we compare these data to data for a similar group of patients with HIV infection alone.
Discussion.
This report indicates that, compared with historical control groups of US children, the HIV-infected cohort was more likely to have HBV or HCV coinfection. Although these findings are not surprising given the shared modes of transmission for the 3 viruses, the children in our study were at least 10 times more likely than the general US pediatric population to have chronic HCV infection. Assuming that the prevalence of chronic HBV infection in the general US pediatric population is <0.42% (the figure for the overall US population), the HIV-infected children studied were also more likely to have HBV infection than were other children [3].
The mono- and coinfected patients shared similar demographic characteristics with respect to race and sex. The mean age of the coinfected patients, however, was higher. We have observed no new perinatal HCV or HBV transmission events over the past decade-a finding attributable to the combined effects of comprehensive screening and prophylaxis. Mothers are routinely screened for hepatitis B surface antigen, and if the tests yield positive results, their infants receive hepatitis B vaccine and immunoglobulin, which are >90% effective in preventing transmission of HBV to newborns [11, 12]. In fact, the incidence of hepatitis B decreased very significantly (by 89%) during 1990-2002 among persons aged 0-19 years [13].
The lower number of documented cases of chronic HCV infection among younger, HIV-exposed birth cohorts indicates the effects of universal screening of blood donors and the expanded use of HAART during pregnancy. Infants are at greater risk of acquiring HCV perinatally if the mother's plasma HCV level is elevated and if the infant becomes infected with HIV [5, 14-16]. Thus, HAART use during pregnancy has decreased the rate of vertical transmission of both HIV and HCV from coinfected women. For the children in this cohort who became HIV infected after 1991, we can only speculate that the rate of HCV coinfection decreased because fewer of their mothers had HCV coinfection, either as a result of improved diagnosis and treatment of HCV infection, as a result of reduced injection drug use, or because blood products were screened. However, because the prevalence of HCV coinfection among the mothers involved in this study was not documented, transmission rates cannot be estimated.
HBV- and HCV-coinfected children tended to be more symptomatic (CDC category C), to have lower CD4 percentages, and to have higher HIV-1 RNA levels than their monoinfected counterparts. We could not assess whether HBV or HCV infection had an impact on HIV disease progression or tolerance to antiretroviral treatment. This is a result of the small number of patients and a patient population that skewed toward older age in the coinfected group. Intolerance to antiretrovirals in HIV-infected adolescents is often complicated by the development of drug resistance, adherence issues, drug toxicity, and psychosocial factors.
Coinfected children were also more likely to have elevated liver function test values. However, nearly 50% of the coinfected children had normal transaminase levels, including a subset of patients who had high-level HBV replication, as determined on the basis of positivity for hepatitis B e antigen. Ideally, liver biopsy specimens would be obtained to determine disease severity and stage, especially in HCV infection, for which such biopsies provide prognostic information. Because only 3 of the children in our study underwent biopsies, this information was not included.
The treatment of coinfected patients is complex and requires a multidisciplinary effort. Only 1 of the 7 HCV-coinfected pediatric patients described in this report was treated for HCV infection, illustrating the guarded general approach to treatment, given the paucity of available information.
In the past 15 years, we have witnessed a remarkable decrease in the rate of perinatal acquisition of HCV and HBV infection. The patients whom we identified as coinfected were primarily adolescents who were exposed before current prevention strategies were available. Nonetheless, given the high prevalence of coinfection documented in this cohort, it would be prudent to screen all HIV-infected adolescents for viral hepatitis. Limitations in sample size and the lack of staging liver biopsies in the cohort described in this report make it difficult to speculate about the potential bidirectional impact of these coinfections on disease progression. Furthermore, without an adequate number of patients, it is not feasible to embark on clinical trials evaluating treatment protocols. This is further complicated by the fact that contemporary pediatric antiretroviral regimens frequently include agents with activity against HIV and HBV-namely, lamivudine, tenofovir, and emtricitabine. Multicenter studies that focus on coinfected adolescents are needed for additional evaluation of this population and to establish guidelines for effective treatment of such patients.
Finally, the focus of our efforts must turn to the developing world-especially in Asia, where the burden of HIV infection and chronic viral hepatitis is greatest [17]. Unfortunately, access to the resources necessary to address these 2 intersecting epidemics is limited in the regions of the world where it is most needed. However, as the net of antiretroviral therapy gradually expands, it will be imperative to institute preventive strategies and to develop guidelines that can effectively manage chronic HBV or HCV infection in HIV-infected children and adolescents.
Methods.
We conducted a chart review of 242 HIV-infected children and adolescents observed at Jacobi Medical Center's pediatric HIV clinic during 2003-2005. The clinic is located in an inner city hospital in Bronx, New York. The children are observed on a regular basis at 1-3-month intervals. HIV-infected children were only included in the study if they were screened adequately for both chronic HBV and HCV infection.
HIV infection was determined on the basis of positive results for at least 2 separate peripheral blood samples for any of the following tests: HIV DNA PCR, HIV viral culture, or HIV EIA (with confirmatory Western blot analysis for children aged >18 months). A child was defined as having chronic HBV infection if their serum tested positive for hepatitis B surface antigen over a 6-month period or longer. HCV infection was determined using a 2-step procedure: reactive HCV antibody results were confirmed using a qualitative HCV RT-PCR. A patient was considered to have chronic HCV infection if the results of both tests were positive.
Information on demographic characteristics, route of HIV transmission, and laboratory values were abstracted from the medical charts. CD4 cell counts, HIV-1 RNA levels, and serum transaminase levels were recorded at the same time point: at the time of diagnosis of HBV or HCV infection or, for HIV-monoinfected patients, at the most recent clinic visit.
Results.
Two hundred twenty-eight patients (94%) met the inclusion criteria. Seven patients had chronic HCV infection (3.1%; 95% CI, 1.4%-6.5%), and 6 patients had chronic HBV infection (2.6%; 95% CI, 1.1%-5.9%). None of the patients were infected with all 3 viruses. Fourteen patients were excluded from the study, because they were not screened for HBV and HCV infection.
Baseline demographic characteristics for the coinfected and monoinfected groups are summarized in table 1. The groups were similar with regards to sex and race. However, the coinfected patients were generally older than their monoinfected counterparts, with mean ages of 16 and 17 years (range, 11-23 years) for the HCV and HBV coinfection groups, respectively, compared with 11.4 years for the monoinfected group.
In the monoinfected cohort, 99% of children acquired HIV vertically. In contrast, 33% of the HBV-HIV-coinfected patients acquired HBV and HIV infections through blood transfusions.
We also compared the Centers for Disease Control and Prevention (CDC) categories, CD4 cell percentages, and HIV-1 RNA levels of the coinfected and monoinfected groups (table 2). A total of 83% and 71% of the HBV- and HCV-coinfected patients, respectively, had HIV infection classified as CDC category C1-C3. Only 21% of the monoinfected children were classified as having category C infection. The coinfected children were also more likely to have lower CD4 cell percentages and higher HIV-1 RNA levels. Of the HBV-coinfected patients, 67% had CD4 cell percentages <15%, and 67% had HIV-1 RNA levels >10,000 copies/mL. Forty-three percent of the HCV-coinfected patients had CD4 cell percentages <15%, and 43% had HIV-1 RNA levels >10,000 copies/mL. In contrast, only 9.8% of the monoinfected patients had CD4 cell percentages <15%, and 27% had elevated HIV-1 RNA levels. The monoinfected children tended to have higher CD4 T lymphocyte counts; 63.7% had CD4 cell percentages >25%, and 39% had undetectable HIV-1 RNA loads.
The HBV- and HCV-coinfected children were more likely to have mildly elevated transaminase levels (i.e., <2-fold greater than the upper limit of normal; 50% and 57%, respectively), compared with the monoinfected group (19%). None of the coinfected children had transaminase levels with >2-fold elevations.
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