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HBV, HBV Vaccinations, and HAART
  "Prevalence of Chronic Hepatitis B and Incidence of Acute Hepatitis B Infection in Human Immunodeficiency Virus Infected Subjects"
The Journal of Infectious Diseases 2003;188:571-577
Scott E. Kellerman,1,a Debra L. Hanson,2 A. D. McNaghten,1,a Patricia L. Fleming1. 1Surveillance Branch and 2Statistics and Data Management Branch, Division of HIV/AIDS Prevention, Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
Abstract: We determined incidence and risk factors for acute and chronic hepatitis B virus (HBV) infection and HBV vaccination rates among human immunodeficiency virus (HIV)infected subjects from the Adult/Adolescent Spectrum of HIV Disease Project, during 1998-2001.
Among 16,248 HIV-infected patients receiving care, the incidence of acute HBV was 12.2 cases/1000 person-years (316 cases), was higher among black subjects (rate ratio [RR], 1.4; 95% confidence interval [CI], 1.02.0), subjects with alcoholism (RR, 1.7; 95% CI, 1.22.3), subjects who had recently injected drugs (RR, 1.6; 95% CI, 1.12.4), and subjects with a history of AIDS-defining conditions (RR, 1.5; 95% CI, 1.21.9) and was lower in those taking either antiretroviral therapy (ART) with lamivudine (RR, 0.5; 95% CI, 0.40.6), ART without lamivudine (RR, 0.5; 95% CI, 0.30.7), or 1 dose of HBV vaccine (14% of subjects) (RR, 0.6; 95% CI, 0.40.9).
Prevalence of chronic HBV was 7.6% among unvaccinated subjects. HBV rates in this population were much higher than those in the general population, and vaccination levels were low.
HBV remains an important cause of comorbidity in HIV-infected persons, but ART and vaccination are associated with decreased disease.
Discussion: In addition, in previous studies, the risk for progression from acute to chronic HBV infection in HIV-infected subjects varied from 21% to 40%, compared with <5% in generally healthy adults. In our cohort of HIV-infected subjects, acute HBV infection progressed to chronic HBV infection in 7% of ASD participants (data not shown). However, in this relatively small number of subjects, we were unable to document that HAART regimens with and without lamivudine have a beneficial effect on progression from acute to chronic HBV infection, despite the biologic plausibility of this hypothesis. How lamivudine effects the process of conversion from acute to chronic HBV infection remains a question for studies specifically designed to evaluate the rate of progression from acute to chronic HBV infection in HIV-infected subjects.
Background: Persons at risk for infection with human immunodeficiency virus (HIV), through high-risk sexual and drug-using behaviors, are at higher risk for acute and chronic hepatitis B virus (HBV) infection. Previous studies have shown high prevalence of acute and chronic HBV infection in subjects at risk for HIV. In addition, persons with HIV infection are at higher risk for HBV-related cirrhosis than are HBV-infected persons without HIV infection, and coinfection with both viruses has been shown to decrease survival time.
Although estimates of HBV prevalence (0.4%) and incidence (0.033 cases /1000 person-years [PY]) in the general US population are available, similar data on rates of HIV and HBV coinfection in the era of highly active antiretroviral therapy (HAART) are limited. Furthermore, since the approval, in 1998, of lamivudine for the treatment of chronic HBV infection, few studies have examined the beneficial effects that lamivudine taken as part of HAART regimens has on chronic HBV, and no published studies have examined the effect that HAART has on the incidence of acute HBV infection in HIV-infected subjects. Finally, vaccination of high-risk persons (e.g., men who have sex with men [MSM] and injection drug users [IDUs]) has been recommended since the early 1990s, and studies suggest that persons with HIV are inadequately vaccinated against a variety of different antigens, including HBV.
In this study, we estimated incidence of acute HBV and prevalence of chronic HBV, in HIV-infected subjects enrolled in the Adult/Adolescent Spectrum of HIV Disease Project (ASD), a longitudinal, medical-recordreview study. In addition, we estimated HBV vaccination rates, determined risk factors for acute HBV infection, and examined the effect that antiretroviral therapy (ART) regimens have on incidence and prevalence of HBV.
Incidence density of acute HBV infection. During July 1998-June 2001, 16,248 subjects with HIV were eligible for the analysis of acute HBV and were followed up for 25,978 PY, during which time 316 cases of acute HBV infection were documented, resulting in a crude incidence density of 12.2 cases/1000 PY.
Risk factors for acute HBV infection. Of the 16,248 subjects followed up during the study period, 2479 (14%) received >1 dose of the hepatitis B vaccine before or during the study period. Multivariate analysis showed higher rates of acute HBV infection among black subjects, subjects with a recent history (i.e., in the 6 months before an observation) of alcohol abuse and/or injection drug use. During the study period, >1 doses of hepatitis B vaccination and prescription of ART or HAART with and without lamivudine were associated with a decreased risk for acute HBV infection; however, the estimated rate ratios of the association between ART or HAART regimens with and without lamivudine and a lower incidence density of acute HBV infection were approximately equal to those of regimens without ART. Low CD4 counts were not significantly associated with acute HBV; however, a previous diagnosis of an AIDS opportunistic infection was associated with a higher incidence density of acute HBV infection.
Prevalence of chronic HBV infection. Among 19,904 subjects eligible for analysis for the presence of chronic HBV infection who were followed up during the study period, we identified 1506 cases of chronic HBV infection, for a 3-year prevalence of 7.6%. The annual prevalences were 7.1%, 7.7%, and 8.0%, during July 1998-June 1999, July 1999-June 2000, and July 2000-June 2001, respectively. The median follow-up time was 42 months. The prevalence of chronic HBV infection was higher among men than among women and was lowest among Hispanics. The highest prevalence, by risk group, was among MSM who were IDUs. Among those ASD participants prescribed ART regimens with lamivudine, the prevalence of chronic HBV was 2.3%, compared with 7.8% among ASD participants who had previously been prescribed ART regimens without lamivudine and 22.1% among participants who had not been prescribed ART before the end of the study period.
DISCUSSION by authors
We determined that, in the United States, 55,600-62,100 persons may be coinfected with chronic HBV/HIV coinfection. Similarly, the approximate range of incident cases of acute HBV infection in HIV-infected personsexcluding those with prevalent chronic HBV infection, those who have been vaccinated against HBV, and those with a previous, resolved acute HBV infection (35%) may be as high as 5100-5700 cases/year. This finding highlights the enormous burden of acute and chronic HBV infection, in light of adverse sequelae from potentially hepatotoxic ART regimens, the lack of integration of HIV- and HBV-prevention efforts, the expanding market for treatment of HBV infection, and the inadequate vaccination of HIV-positive persons. Despite reported decreases in HBV seroincidence among high-risk groups decreases associated with the adoption of safer sex practices and the availability of an effective HBV vaccine the results of this study confirm that HIV-infected persons remain at risk for HBV infection.
Although studies performed a decade ago have shown HBV/HIV coinfection rates to be >50% in some high-risk populations, these estimates were derived from cohorts studied before the widespread use of HBV vaccine and potent HAART regimens. More-recent studies, of smaller cohorts, in the United States and Europe have reported prevalence estimates of chronic HBV that range from <7% to 9%.
It is not surprising that higher rates of HBV infection might be found in IDUs, given that injection drug use is a highly efficient mode of HBV transmission. Subjects with a recent history of alcohol abuse might also be expected to have higher rates of diagnosed acute HBV infection, since they are more likely to have hepatitis serologies performed, as a result of higher levels of liver enzymes. Alternately, subjects with a history of alcohol abuse may be more likely to engage in high-risk behaviors. Finally, the higher rate of acute HBV infection among subjects with a history of an AIDS opportunistic infection may reflect more-intensive medical follow-up of the patient, increased severity of disease (resulting in a more-extensive clinical evaluation), or reactivation of a previously unknown case of HBV infection.
Lamuvudine has been shown to inhibit HBV replication in >80% of infected subjects with or without HIV coinfection. Subjects prescribed ART regimens with or without lamivudine had lower rates of chronic HBV than did subjects with no history of being prescribed ART. With regard to lamivudine treatment of HBV/HIV coinfected subjects, several researchers have addressed the issues of dosing, dual treatment of HIV infection and HBV infection, and emergence of lamivudine-resistant strains of HBV, but studies specifically examining the effects of lamivudine and newer anti-HBV compounds are needed. It is possible that differences in duration of observation of subjects receiving and not receiving lamivudine could bias our findings, because longer follow-up was related to higher prevalence rates. However, when we controlled for length of observation, our results did not change (data not shown).
Given the effect that lamivudine has in the prevention of reinfection after liver transplantation, we expected lamivudine-containing ART regimens to confer protection against acute HBV infection. However, rates of acute HBV infection were similar, regardless of whether the ART regimens contained lamivudine. This finding suggests that, in our study, in decreasing the acquisition of acute HBV infection, ART regimens with lamivudine were no more effective than those without lamivudine. This negative finding may be explained if it is found that health-care providers had systematically decided to use lamivudine-containing HAART regimens to treat those subjects perceived to be at highest risk for HBV infection (i.e., a situation of confounding by intention). If this were so, then the additional protective effect of lamivudine that is seen in the analysis of prevalence would not be seen in the analysis of incidence, because those at greatest risk would already be protected. Unfortunately, information with regard to why particular regimens have been prescribed is not routinely entered into the medical record and therefore is not available for data abstraction. To adequately identify the question of the effect that lamivudine has on acquisition of acute HBV infection, a randomized clinical trial would be the most appropriate study design.
Because ASD participants are not systematically screened for markers of HBV infection, our data-collection methods may have underascertained cases of acute HBV infection, primarily those which were subclinical or mildly symptomatic (estimated to be 30% in affected adults of unknown HIV status). In addition, cases of prevalent HBV may not have been identified if HBV infection occurred either before HIV diagnosis or before a patient had received care at an ASD facility. In addition, acute HBV was defined as IgM antibody to the surface antigen, not as antihepatitis B core IgM. As a result, some acute HBV infections may have been reactivations of chronic HBV disease.
In developed countries, the introduction of potent new ART regimens has changed the course of the HIV epidemic. Because HBV and HIV are transmitted via the same routes, new cases of acute HBV infection, in persons known to have HIV infection, suggest that some HIV-infected persons do not adhere to traditional risk-reduction messagesthat is, safe sex and/or safe injection practices. This finding suggests that prevention messages designed to decrease HIV transmission may not be effective or may be less effective, in the prevention of new comorbid infections such as HBV. Prevention programs specific for HIV-infected persons, such as the Serostatus Approach to Fighting the HIV Epidemic (SAFE) Initiative being developed by the CDC, will focus prevention efforts on HIV-infected persons, as well as on HIV-negative persons at high risk
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