Abstract
Background
The epidemiologic trends of hepatitis B virus (HBV) infection in HIV-infected patients over the last twenty years are largely unknown.
Methods
Prevalence and risk factors for HBV infection overall, at the time of HIV infection, and following HIV infection were examined in an ongoing observational HIV cohort study. Risk factors for HBV infection at the time of HIV diagnosis were evaluated using logistic regression, and risk for incident HBV infection following HIV diagnosis was evaluated using Cox proportional hazards models.
Results
Of the 2769 evaluable participants, 1078 (39%) had HBV infection, of which 117 (11%) had chronic HBV. The yearly cross-sectional prevalence of HBV infection decreased from a peak of 49% in 1995 to 36% in 2008 (p<0.001). HBV prevalence at the time of HIV diagnosis decreased between 1989 and 2008 from 34% to 9% (p<0.001). The incidence of HBV infection following HIV diagnosis decreased from 4.0/100 person-years in the pre-HAART era to 1.1/100 person-years in the HAART era (p<0.001), but has remained unchanged from 2000 through 2008 (p=0.49), with over 20% of incident HBV infections having chronic HBV. Decreased risk of HBV infection following HIV diagnosis was associated with higher CD4 cell counts and the use of HBV-active HAART. Receipt of ≥1 dose of HBV vaccine was not associated with reduced risk of HBV infection after HIV diagnosis.
Conclusions
While the burden of HBV infection overall is slowly decreasing among HIV-infected individuals, the persistent rate of HBV infection following HIV diagnosis raises concern that more effective prevention strategies may be needed to significantly reduce HBV infections in this patient population.
Keywords: Hepatitis B Virus, Human Immunodeficiency Virus, Sexually Transmitted Infections, Highly Active Antiretroviral Therapy, Hepatitis B Vaccine
Introduction
Liver-related complications have become an increasingly important cause of morbidity and mortality in HIV-infected patients since the advent of highly active antiretroviral therapy (HAART)[1,2], with one study showing 15% of deaths in HIV-infected adults related to liver disease.[3] Co-infection with hepatitis B virus (HBV) is a well recognized cause of liver-related complications in individuals with HIV, and is associated with an increased risk of mortality.[4,5,6,7,8] Active co-infection with HIV and HBV significantly influences the use of HAART in such patients, impacting the selection and timing of antiretroviral initiation,[9,10] and increasing HAART-related hepatotoxicity risk.[11,12,13]
Given the significant burden and clinical impact of HBV in HIV-infected individuals, understanding the epidemiologic trends and risk factors associated with HBV infection in HIV-infected populations are crucial. The prevalence of positive HBV serological markers has been reported to be as high as 80% in some HIV-infected populations, with a chronic HBV prevalence of up to 10%.[6] However, currently available data are somewhat limited. Previous investigations defined chronic HBV infection using a single positive hepatitis B surface antigen (HBsAg) result without including other serological markers and reported only prevalent cross-sectional data.[7,14,15,16,17,18,19] Data on incident HBV infection in HIV-infected individuals, especially, remains limited, but such data could improve our understanding of HBV transmission and offer opportunities for improving HBV prevention in HIV-infected adults. One study reported the incidence of acute HBV infection in a large HIV cohort as 12.2 cases per 1000 person-years, and a chronic HBV prevalence of 7.6%.[20] This study, however, used a window of observation from 1998–2001, and the proportion of infections which ultimately become chronic was not reported.
While the overall prevalence of HBV in the U.S. is likely underestimated [21,22], data indicate a decreasing overall incidence of acute HBV in the general U.S. population over the last two decades.[23,24] However, similar data assessing HBV infection trends in HIV-infected individuals have not been published to our knowledge. Therefore, the aim of this study was to describe the epidemiology of HBV infection in a prospective, observational cohort, the U.S. Military HIV Natural History Study (DoD NHS). Our specific objectives were to (1) examine the prevalence of HBV infection by year, (2) determine the prevalence of and factors associated with HBV infection present at the time of HIV diagnosis, and (3) evaluate the incidence of and factors associated with HBV infection after HIV diagnosis.
Methods
Participants
The DoD NHS is a previously described, ongoing, continuous enrollment observational cohort of HIV-infected DoD beneficiaries in existence since 1986, with over 4,900 participants.[25,26] All active duty military members and their adult dependents with a diagnosis of HIV infection who are seen at participating sites and able to provide written consent, are eligible for participation. Because of military patient referral patterns and continued study participation as civilians following completion of military service, participants in the DoD NHS represent a broad cross-section of the adult U.S. population, from all regions of the country. HIV exposure category is not routinely captured, although one previous study suggested that injection drug use in this cohort is rare.[27] Approval for this research was obtained from the institutional review board at each participating site.
Definitions and Inclusion
HBV infection was defined as meeting at least one of the following criteria: 1) concurrently reactive for HBsAg and hepatitis B core antibody (HBcAb), 2) concurrently reactive for HBcAb and hepatitis B surface antibody (HBsAb), or 3) reactive for HBsAg or HBcAb on two separate occasions. Chronic HBV infection was defined as having a reactive HBsAg on two separate occasions at least 6 months apart. A participant was classified as HBV-uninfected at the time of HIV diagnosis if both HBsAg and HBcAb tests were initially non-reactive on or after the date of HIV diagnosis.
As HBV screening became uniform in 1989, those enrolled prior to 1989 were excluded from all analyses. Participants without a documented date of HIV diagnosis and those whose HBV infection status could not be determined at any time were also excluded (Figure 1). For the evaluations of HBV infection at the time of HIV diagnosis and incidence of HBV infection after HIV diagnosis, two different, partially overlapping subgroups of participants were defined a priori.
Figure 1.
Flow diagram of participant selection for three analysis groups (see Methods). HBV, hepatitis B virus, NHS, Natural History Study, HIV, human immunodeficiency virus
For analyses, ethnicity was categorized as Caucasian, African American, Hispanic/Puerto Rican/Mexican, or other. An individual was considered to have a sexually transmitted infection (STI) if there was a medical history or laboratory evidence of syphilis, genital herpes, gonococcal, or chlamydial infection. The presence of an AIDS-defining illness was defined using 1993 CDC criteria, with the exception of an isolated CD4 count <200 cells/μL.[28] HAART was defined similar to previous studies.[24] Antiretroviral therapy (ART) was categorized as none, mono/dual ART or HAART. Mono/dual ART and HAART categories were further sub-divided as HBV-inactive and HBV-active, with HBV-active therapy defined as the use of lamivudine, emtricitabine or tenofovir. Hepatitis B vaccination was defined as receipt of ≥1 vaccine dose.
Design and Statistical Analysis
Descriptive statistics were used to describe the eligible participants overall, and the two subgroups. Medians were given with interquartile ranges (IQR). Proportions were compared with chi-squared tests. To address the three main objectives of the study, three analyses were conducted. To determine the prevalence of HBV infection by year in our cohort, we examined the participants meeting the criteria listed above for overall inclusion. For these participants, the yearly cross-sectional prevalence of HBV and chronic HBV infection was calculated by determining the proportion of participants seen in a particular year with serologic evidence of HBV infection in that year or prior. Changes in prevalence over time were examined using the Cochran-Armitage test for trend.
For the second objective, the prevalence of and risk factors for HBV infection at the time of HIV diagnosis were determined for the subgroup of participants with known recent HIV infection (defined as having a documented HIV seroconversion window of ≤3 years) and known HBV status within 6 months after HIV diagnosis. Univariate and multivariate logistic regression models were used to examine HBV infection risk for this group. For sensitivity analyses, the models were repeated separately for HIV-diagnosis era subgroups: the pre-HAART era (before 1996) and the HAART era (1996 or later).
For the third objective, the incidence of and risk factors for HBV infection after HIV diagnosis were determined for all eligible HIV-positive participants (not just HIV seroconverters) who were known to be HBV negative at the time of HIV diagnosis. Participants were followed from HIV diagnosis until HBV infection or last study visit. The number of HBV and chronic HBV events, person years at risk and rates (per 100 person-years of follow-up) were calculated for the entire study period and for specific time intervals (pre- and HAART eras). Poisson regression analyses were used to test differences in rates over those intervals. Univariate and multivariate Cox proportional hazards models, stratified by HIV diagnosis era (pre-HAART or HAART), were used to explore the relationship between factors and incident HBV infection risk. Time-updated covariates utilized all available measurements during the period of observation.
Significance was defined a priori as p<0.05; all p-values were two-sided. Age, gender, and ethnicity were included in all multivariate models along with variables that were significant in univariate analyses (at p<0.05). Odds ratios (OR), hazard ratios (HR), and rates were presented with 95% confidence intervals (95% CI). All analyses were conducted using SAS software (version 9, SAS Institute, Inc., Cary, North Carolina). All figures were generated using the R programming language (version 2.0.0). The “loess” and “predict.loess” functions in R were used to generate the local linear robust fit smoothing lines and pointwise 95% confidence intervals depicting both the prevalence and incidence of HBV and chronic HBV infection.[29]
Results
Prevalence of HBV infection overall
Among the 2,769 participants included in the analysis, the median number of HBV screens per participant was four (IQR, 2–9), and the median interval between HBV screens was 6.4 months (IQR, 5.6–10.1). The median interval from the last HBV screen to censoring was 1.2 months (IQR, 0–12.2). Characteristics of eligible participants are shown in Table 1. Crude mortality was higher in the pre-HAART era (28.2%) than the HAART era (1.8%), but similar by HBV status (pre-HAART era, 29.0% for HBV-infected, 27.4% for HBV-uninfected; HAART era, 3.5% for HBV-infected, 1.2% for HBV-uninfected). Annual rates of enrollment and study discontinuation in the pre-HAART and HAART eras were similar regardless of HBV status (data not shown).
Table 1.
Characteristics at the time of HIV diagnosis among participants by analysis group.*
| N | Overall HBV Prevalence (N=2769) | Prevalence of HBV at HIV diagnosis (N=1885) | Incidence of HBV after HIV diagnosis (N=1872) | |
|---|---|---|---|---|
| HIV diagnosis date, median (IQR) | 2769 | Mar 1995 (Aug 1991 – Feb 2001) | Aug 1996 (Jan 1992 – Jan 2002) | Aug 1996 (Mar 1992 – Feb 2002) |
| Age, years, median (IQR) | 2769 | 28.7 (24.0 – 35.1) | 27.2 (23.3 – 32.9) | 27.2 (23.3 – 33.0) |
| Male, n (%) | 2769 | 2512 (90.7) | 1785 (94.7) | 1647 (88.0) |
| Self-identified ethnicity, n (%); | 2768 | |||
| Caucasian | 1204 (43.5) | 805 (42.7) | 818 (43.7) | |
| African American | 1224 (44.2) | 855 (45.4) | 812 (43.4) | |
| Hispanic or Puerto Rican or Mexican | 236 (8.5) | 159 (8.4) | 166 (8.9) | |
| Asian or Pacific Islander | 46 (1.7) | 29 (1.5) | 32 (1.7) | |
| Native American or Alaskan Native | 16 (0.6) | 9 (0.5) | 11 (0.6) | |
| Other | 42 (1.5) | 28 (1.5) | 32 (1.7) | |
| CD4 cell count, cells/μL, median (IQR) | 2477 | 490 (339 – 649) | 507 (373 – 659) | 494 (349 – 651) |
| HIV RNA, log10 copies/mL, median (IQR) | 1519 | 4.4 (3.7 – 4.9) | 4.4 (3.7 – 4.8) | 4.3 (3.7 – 4.9) |
| AIDS-defining illness, n (%) | 2769 | 89 (3.2) | 20 (1.1) | 48 (2.6) |
| Hepatitis C positive, n (%) | 1815 | 55 (3.0) | 30 (2.2) | 27 (2.1) |
| Previous sexually transmitted infection, n (%) | 2756 | 871 (31.6) | 584 (31.1) | 513 (27.5) |
| Gonorrhea, n (%) | 2760 | 457 (16.6) | 294 (15.6) | 244 (13.1) |
| Chlamydia, n (%) | 2763 | 278 (10.1) | 209 (11.1) | 176 (9.4) |
| Herpes, n (%) | 2768 | 126 (4.6) | 87 (4.6) | 80 (4.3) |
| Syphilis, n (%) | 2769 | 255 (9.2) | 152 (8.1) | 124 (6.6) |
| Prior receipt of HBV vaccine, n (%) | 2769 | 512 (18.5) | 421 (22.3) | 436 (23.3) |
| HBV infected, n (%)† | 2769 | 1078 (38.9) | 456 (24.2) | 181 (9.7) |
| Chronic HBV infected, n (%)‡ | 2769 | 117 (10.9) | 33 (7.2) | 37 (20.4) |
HBV, hepatitis B virus; HIV, human immunodeficiency virus
See Figure 1 and Methods for inclusion and exclusion criteria for each analysis group.
For Overall HBV prevalence, number HBV infected ever; For Prevalence of HBV at HIV diagnosis, number HBV at the time of HIV diagnosis only; For Incidence of HBV after HIV diagnosis, number HBV infected any time after HIV diagnosis.
Of those with HBV infection, number with chronic HBV infection (percent of HBV infections which were chronic).
Of the 2,769 participants, 1,078 (38.9%) were HBV-infected over the entire observation period, and of these, 117 (10.9%) had chronic HBV. During each year, approximately 40% of those seen were infected with HBV (Figure 2). The cross-sectional prevalence of HBV and chronic HBV peaked in 1995 (49.2% and 6.8%, respectively). Since 1996, the cross-sectional prevalence of HBV and chronic HBV infection have both decreased significantly (p <0.001 for each comparison). The overall prevalence of chronic HBV among unvaccinated and vaccinated participants seen in the HAART era was 6.8% and 2.3%, respectively (p<0.0001). The estimated prevalence of chronic HBV infection reached its lowest level in 2008 at 3.9% (95% CI 3.1–4.6).
Figure 2.
Cross-sectional prevalence of HBV and chronic HBV infection by calendar year for participants with serological HBV assessment (N=2769). (p<0.001 for trend for both HBV and chronic HBV prevalence).
The solid and dotted lines represent the local linear robust fit smoothing line and the pointwise 95% confidence intervals respectively for the prevalence at the time of HBV diagnosis of both HBV and chronic HBV. Participants could contribute to every year for which they were seen and evaluated.
HBV, hepatitis B virus, HAART, highly active antiretroviral therapy.
Prevalence of HBV infection at the time of HIV diagnosis
Of the 1,885 participants with recent HIV infection (HIV seroconversion ≤3 years) and known HBV status at the time of HIV diagnosis, 456 (24.2%) were HBV-infected and of these, 33 (7.2%) had chronic HBV. The prevalence of HBV and chronic HBV at the time of HIV diagnosis decreased between 1989 and 2008 (Figure 3; p<0.001 for HBV; p=0.002 for chronic HBV). In multivariate analysis (Table 2), a higher risk of HBV infection at the time of HIV diagnosis was associated with older age (OR 2.03, 95% CI 1.72–2.40 per 10-year increase), male gender (OR 7.15, 95% CI 2.58–19.82), and a prior history of gonorrhea (OR 1.92, 95% CI 1.44–2.56) or syphilis (OR 1.63, 95% CI 1.11–2.38). Receipt of HBV vaccine prior to HIV diagnosis was associated with reduced risk (OR 0.33, 95% CI 0.24–0.46). When included in the multivariate model, HCV status (unknown for 28% of participants) was not associated with risk of HBV infection (HR 1.56, 95% CI 0.68–3.58); results including HCV status were otherwise similar (data not shown). Separate multivariate analyses for those with HIV diagnosis in the pre-HAART era and HAART era had similar results (data not shown).
Figure 3.
Prevalence of HBV and chronic HBV at the time of HIV diagnosis by year among participants with known recent HIV infection (defined as documented HIV seroconversion within the preceding three years) and HBV serological assessment within 6 months of HIV diagnosis (N=1885). (for HBV, p<0.001 for trend; for chronic HBV, p=0.002 for trend)
The solid and dotted lines represent the local linear robust fit smoothing line and the pointwise 95% confidence intervals respectively for the prevalence at the time of HBV diagnosis of both HBV and chronic HBV. Participants could only contribute to the year in which they were diagnosed with HIV. HBV, hepatitis B virus, HAART, highly active antiretroviral therapy.
Table 2.
Risk of hepatitis B infection at the time of HIV diagnosis among 1885 participants with a known HIV seroconversion window ≤3 years and known HBV status at the time of HIV diagnosis.
| N† | Univariate Models* | Multivariate Model* | |||
|---|---|---|---|---|---|
| Risk factor at the time of HIV diagnosis | OR (95% CI) | P-value | OR (95% CI) | P-value | |
| Age, per 10-year increase | 1885 | 2.07 (1.78 – 2.42) | <0.001 | 2.03 (1.72 – 2.40) | <0.001 |
| Male gender | 1885 | 8.13 (2.98 – 22.23) | <0.001 | 7.15 (2.58 – 19.82) | <0.001 |
| Ethnicity | |||||
| Caucasian | 805 | Ref | Ref | ||
| African American | 855 | 0.89 (0.71 – 1.12) | 0.32 | 0.95 (0.75 – 1.21) | 0.68 |
| Hispanic or Puerto Rican or Mexican | 159 | 0.69 (0.45 – 1.05) | 0.08 | 0.74 (0.47 – 1.15) | 0.18 |
| Other | 66 | 0.51 (0.25 – 1.01) | 0.05 | 0.58 (0.29 – 1.19) | 0.14 |
| CD4 cell count, per 100 cells/μL increase | 1745 | 1.00 (0.96 – 1.04) | 0.94 | ||
| HIV RNA, per 1 log10 increase | 1158 | 1.03 (0.88 – 1.21) | 0.72 | ||
| AIDS-defining illness | 1885 | 2.11 (0.86 – 5.20) | 0.10 | ||
| Hepatitis C positive | 1361 | 2.27 (1.09 – 4.71) | 0.03 | ||
| Previous sexually transmitted infection | |||||
| Any | 1877 | 1.84 (1.48 – 2.30) | <0.001 | ||
| Gonorrhea | 1880 | 2.32 (1.78 – 3.02) | <0.001 | 1.92 (1.44 – 2.56) | <0.001 |
| Chlamydia | 1881 | 1.45 (1.06 – 1.98) | 0.02 | 1.24 (0.88 – 1.75) | 0.22 |
| Herpes | 1884 | 1.06 (0.65 – 1.74) | 0.81 | ||
| Syphilis | 1885 | 2.07 (1.46 – 2.92) | <0.001 | 1.63 (1.11 – 2.38) | 0.01 |
| Prior receipt of HBV vaccine | 1885 | 0.36 (0.26 – 0.49) | <0.001 | 0.33 (0.24 – 0.46) | <0.001 |
Logistic regression models
Number of participants with data available by characteristic
Incidence of HBV infection after HIV infection
Of the 1,872 participants who were HBV negative at the time of HIV diagnosis, 181 (9.7%) became HBV infected during follow-up and of these, 37 (20.4%) developed chronic HBV (p<0.001 compared to the 7.2% of patients with HBV infection at the time of HIV diagnosis that were chronic). There were 2,521 and 7,301 years of follow-up available in the pre-HAART and HAART eras respectively. The rate of incident HBV in the pre-HAART era (4.0 per 100 person years of follow-up (PY); 95% CI 3.2–4.7) was significantly higher than the rate in the HAART era (1.1 per 100 PY; 95% CI 0.9–1.4) (p<0.001; Figure 4). Similarly, the rate of chronic HBV in the pre-HAART era (1.2 per 100 PY; 95% CI 0.7–1.6) was significantly higher than the rate in the HAART era (0.12 per 100 PY; 95% CI 0.03–0.19) (p<0.001). The rate of incident HBV infection appeared to increase from 2000 to 2008, but this trend was not significant (p=0.49).
Figure 4.
Incidence of HBV infection after HIV diagnosis for HIV-seroprevalent participants who were HBV sero-negative at the time of HIV diagnosis (N=1872). (For comparing the rate of HBV in the pre-HAART era to the HAART era, p<0.001. The rate of chronic HBV in the pre-HAART era was 1.2 per 100 PY (95% CI 0.7–1.6) compared to 0.12 per 100 PY (95% CI 0.03–0.19) for the HAART era (p<0.001).
The solid and dotted lines represent the local linear robust fit smoothing line and the pointwise 95% confidence intervals respectively for the incidence of both HBV and chronic HBV. Participants could contribute to every year for which they were seen and evaluated until last study visit or the occurrence of HBV infection. HBV, hepatitis B virus, HAART, highly active antiretroviral therapy.
From time-to-event models (Table 3), multivariate risk of incident HBV infection was significantly increased for males (HR 7.79, 95% CI 2.86–20.86). Risk was significantly reduced for those with higher CD4 cell counts during follow-up (HR 0.90, 95% CI 0.84–0.96 per 100-cell increase) and those on HAART containing HBV-active agents (HR 0.31, 95% CI 0.19–0.51) compared to no ART therapy. Those receiving mono/dual therapy containing HBV-active agents also had reduced risk of incident HBV infection(HR 0.23, 95% CI 0.07–0.72), while those on HAART not containing HBV-active drugs did not have a significantly reduced risk of HBV infection, although there were only 3 and 4 HBV infections in these two subcategories, respectively. Ever receiving ≥1 dose of vaccine was not associated with reduced risk of infection (HR 0.86, 95% CI 0.62–1.18). When included in the multivariate model, HIV RNA during follow-up (unknown for 12% of participants as this test was not widely available prior to 1996) was not associated with risk of HBV infection (HR 1.14, 95% CI 0.92–1.40 per 1 log10 copies/mL increase); results including HIV RNA were otherwise similar (data not shown).
Table 3.
Risk of incident hepatitis B infection among 1872 participants known to be HBV negative at the time of HIV diagnosis.
| N‡ | Univariate Models* | Multivariate Models* | |||
|---|---|---|---|---|---|
| Risk factor | HR (95% CI) | P-value | HR (95% CI) | P-value | |
| Age at HIV diagnosis, per 10-year increase | 1872 | 0.82 (0.66 – 1.01) | 0.06 | 0.84 (0.67 – 1.04) | 0.11 |
| Male gender | 1872 | 7.81 (2.90 – 21.02) | <0.001 | 7.79 (2.86 – 20.86) | <0.001 |
| Ethnicity | |||||
| Caucasian | 818 | Ref | Ref | ||
| African American | 812 | 1.36 (1.01 – 1.85) | 0.05 | 1.33 (0.98 – 1.82) | 0.07 |
| Hispanic or Puerto Rican or Mexican | 166 | 0.76 (0.38 – 1.52) | 0.44 | 0.68 (0.34 – 1.36) | 0.28 |
| Other | 75 | 0.76 (0.28 – 2.07) | 0.59 | 0.84 (0.31 – 2.30) | 0.74 |
| CD4 cell count, per 100 cells/μL increase† | 1869 | 0.92 (0.87 – 0.98) | 0.006 | 0.90 (0.84 – 0.96) | 0.001 |
| HIV RNA, per 1 log10 increase† | 1640 | 1.43 (1.20 – 1.69) | <0.001 | ||
| AIDS–defining illness† | 1872 | 0.64 (0.30 – 1.38) | 0.26 | ||
| Hepatitis C at time of HIV diagnosis | 1292 | 0.96 (0.24 – 3.89) | 0.95 | ||
| Sexually transmitted infection† | |||||
| Any | 1865 | 1.24 (0.92 – 1.68) | 0.15 | ||
| Gonorrhea | 1867 | 1.08 (0.75 – 1.56) | 0.68 | ||
| Chlamydia | 1867 | 1.33 (0.89 – 1.99) | 0.16 | ||
| Herpes | 1872 | 0.84 (0.46 – 1.51) | 0.55 | ||
| Syphilis | 1872 | 1.65 (1.09 – 2.51) | 0.02 | 1.49 (0.97 – 2.29) | 0.07 |
| Antiretroviral (ART) use† | |||||
| None | 623 | Ref | Ref | ||
| Mono/dual ART | 223 | 0.93 (0.64 – 1.37) | 0.73 | 0.77 (0.51 – 1.16) | 0.22 |
| HBV-active mono/dual ART | 78 | 0.26 (0.08 – 0.82) | 0.02 | 0.23 (0.07 – 0.72) | 0.01 |
| HAART | 59 | 0.43 (0.15 – 1.21) | 0.11 | 0.41 (0.14 – 1.15) | 0.09 |
| HBV-active HAART | 889 | 0.31 (0.19 – 0.50) | <0.001 | 0.31 (0.19 – 0.51) | <0.001 |
| Receipt of HBV vaccine† | 1872 | 0.86 (0.62 – 1.18) | 0.34 | ||
Proportional hazards models, stratified by HIV diagnosis era (prior to 1996 versus 1996 or later)
Time-updated variables, using all available measurements from time of HIV diagnosis until HBV infection or censoring date
Number of participants with data available by characteristic at the time of censoring (HBV infection or last visit)
HBV = hepatitis B virus
Discussion
This comprehensive examination of the epidemiology of HBV infection in a large cohort of HIV-infected individuals highlights the continued and significant burden of HBV infection in HIV-infected adults, with nearly 40% of those with HIV also co-infected with HBV. Despite the gradual decrease in prevalence of chronic HBV infection over the last two decades, overall 11% of those with HBV had chronic HBV. Furthermore, HBV infections following HIV diagnosis continue to occur, and while such infections with HBV have decreased in the HAART era, incidence rates have remained unchanged for the last eight years suggesting additional efforts will be needed to reduce the incidence rate of HBV co-infection further. Lastly, susceptibility to HBV appears to be inversely correlated with immune function, further compounding HBV prevention efforts for HIV-infected individuals.
Decreased HBV prevalence at the time of HIV diagnosis combined with decreased, but now stable incidence of HBV after HIV diagnosis has resulted in a decreasing overall burden in our cohort, or yearly cross-sectional prevalence, of HBV. Unfortunately, despite the gradual decline in HBV prevalence overall in our cohort, prevalence, including that of chronic disease, remains high. A previous U.S. cohort study from the HAART era reported the prevalence of chronic HBV among HBV unvaccinated participants as 7.6%[20], which compares with the 6.8% prevalence of chronic HBV among unvaccinated participants seen in the HAART era in our study. Other investigations have reported similar estimates for the prevalence of chronic HBV among HIV-infected individuals.[6] In addition, AA ethnicity was not clearly associated with increased risk of HBV, similar to recent U.S. trends showing decreasing racial disparities in acute HBV incidence. [23] Furthermore, the association of immunologic function, as reflected by CD4 cell count, with HBV susceptibility suggests the high prevalence of HBV infection in this population may not be only due to similar modes of transmission for HIV and HBV, but also a possible increased susceptibility to HBV in HIV-infected individuals.
Our analysis helps improve the understanding of HBV transmission in individuals with HIV. For HBV infection diagnosed at the time of HIV diagnosis, reflective of HBV transmission prior to HIV diagnosis, data are encouraging. Prevalence has decreased significantly in the last 20 years and is continuing to decline, perhaps reflective of recent U.S. acute HBV infection epidemiologic trends.[23,24] As these infections occurred on an individual level prior to HIV-associated immune dysfunction, prior receipt of HBV vaccine was associated with reduced risk, and a minority of these infections became chronic. However, this model differs from that of HBV transmission after HIV infection. For HBV infections acquired after HIV diagnosis, and therefore after the development of HIV-associated immune dysfunction, one in five resulted in chronic HBV, and vaccine effectiveness may be reduced.[30] While the interpretation of observational data must always be cautious, our results suggest both increased use of vaccination in high-risk HIV-negative populations and improved behavioral interventions in those with HIV would best reduce the burden of HBV infection in adults with HIV. Efforts to address only one transmission model may be only partially effective in reducing the overall burden of HBV in HIV-infected individuals, and effective prevention methods in one model may not necessarily be effective in the other due to differences, including altered immunocompetence.
Although generally lower in the HAART era, the incidence of HBV infections after HIV diagnosis remained unchanged from 2000 to 2008, approximately 100-fold higher than the rate of HBV in the U.S. military, and 500-fold higher than the rate of acute HBV in the general U.S. population.[24,31] The reasons for a lack of continued decline in incident HBV in our cohort are not clear, but this observation is similar to recent trends for other STIs in the general U.S. population.[32,33] The association between HBV infection and STIs in our study supports the conclusion that HBV is acquired predominantly through sexual transmission in our cohort before and likely after HIV diagnosis. The presumed sexual transmission of HBV infection following HIV diagnosis emphasizes the need for improved methods for effective behavioral risk reduction counseling for patients with HIV. Various intervention methods have been shown to impact sexual behavior and reduce risk of incident STIs in HIV-positive and HIV-negative adults.[34,35] Incorporating HIV prevention counseling into the routine medical care of HIV-infected individuals is recommended.[36] Such strategies are important for both prevention of HIV transmission and prevention of other co-infections, such as HBV. Without improved prevention efforts, incident HBV infection among HIV-positive individuals will likely continue to occur.
Intriguingly, the associations between a reduced risk of incident HBV infection and both higher CD4 cell counts and use of HBV active ART/HAART, suggest HBV susceptibility is impacted by both immunologic and virologic factors. Our results agree with a previous investigation which found reduced risk of acute HBV in HIV-infected individuals associated with use of HAART and other ART.[20] Our findings suggest there is a potential HBV preventive benefit of HBV-active HAART in HIV-infected individuals not infected with HBV, and provide evidence of a possible non-traditional benefit from HAART, specifically reduced susceptibility to HBV infection for an individual, and reduced incidence of HBV infection for a population.
As a cohort analysis, our study has limitations. Some characteristics of the DoD NHS cohort may limit comparison to other patient settings, including the limited number of females and injection drug users, the inability to systematically collect sexual risk behaviors, and the high CD4 cell counts of participants at the time of HIV diagnosis due to routine military screening. However, we feel our findings are generalizable because our participants, both active duty and civilian, are representative of a large cross-section of the U.S. adult population, and our findings are in agreement with epidemiologic data regarding HBV and other STIs in the U.S. Second, HBV serologies in HIV-infected individuals may fluctuate[37] making diagnosis and classification for investigation difficult, however, participants in our study received periodic testing of HBV serological markers, and our criteria for inclusion and definitions for infection required results from multiple serologies. In addition, as an observational study, ART and vaccinations are not randomly administered, precluding our ability to determine the direct effects of either ART or vaccination upon HBV acquisition. Finally, some groups had relatively few events limiting some comparisons and conclusions.
Among HIV-infected individuals in the U.S., the prevalence of HBV infection including chronic HBV is gradually decreasing overall, yet it remains substantial. More worrisome is the finding that HIV-infected individuals are continuing to develop incident HBV infection at a rate which has remained unchanged for the last eight years, and appears to result from continued high risk sexual behavior. Effective prevention methods are needed and must overcome the effects of HIV-associated immune dysfunction on HBV transmission and vaccine effectiveness. The associations of HBV-active HAART use and higher CD4 cell counts with decreased risk of incident HBV infection suggest additional benefits of HAART, and provides further rationale for its increased use.
Members of the Infectious Disease Clinical Research Program HIV Working Group
National Institute of Allergy and Infectious Diseases, Bethesda, MD: M. Polis, J. Powers, E. Tramont.
Naval Medical Center, Portsmouth, VA: J. Maguire, V. Barthel, S. Patel.
Naval Medical Center, San Diego, CA: B. Hale, N. Crum-Cianflone, M. Bavaro, H. Chun.
National Naval Medical Center, Bethesda, MD: T. Whitman, A. Ganesan.
San Antonio Military Medical Center, San Antonio, TX: V. Marconi, M. Landrum, J. Delmar, W. Bradley.
Tripler Army Medical Center: A. Johnson.
University of Minnesota, Minneapolis, MN: A. Lifson, K. Hullsiek, A. Fieberg.
Uniformed Services University of the Health Sciences, Bethesda, MD: S. Wegner, B. Agan, G. Martin.
Walter Reed Army Institute of Research, Silver Spring, MD: N. Michael, M. Milazzo, R. O’Connell, S. Peel.
Walter Reed Army Medical Center, Washington, DC: G. Wortmann, C. Hawkes, A. Weintrob, S. Fraser.
Acknowledgments
These data were presented in part at the 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 3-6, 2008. Abstract #1028.
The authors would like to express our gratitude to the members of the IDCRP HIV Working Group including the long line of military HIV researchers who have supported the HIV NHS, and to the research coordinators and support staff for their countless hours of work. Most importantly, we would like to thank the patients for their participation, without who this research would not have been possible.
Support for this work was provided by the Infectious Disease Clinical Research Program (IDCRP) of the Uniformed Services University of the Health Sciences (USUHS). The IDCRP is a DoD tri-service program executed through USUHS and the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), in collaboration with HHS/NIH/NIAID/DCR through Interagency Agreement HU0001-05-2-0011. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting the views of the Departments of the Army, Navy, Air Force, or the Department of Defense. The authors have no commercial or other association that might pose a conflict of interest.
Footnotes
Disclosures: The authors have no commercial or other association that might pose a conflict of interest.
Authorship contribution: Conception and Design: Chun, Landrum
Data acquisition: Bradley, Chun, Landrum, Ganesan, Weintrob, Crum-Cianflone, Barthel, Agan
Statistical analysis: Fieberg, Hullsiek, Landrum, Chun, Lifson
Data analysis and Interpretation: Chun, Landrum, Lifson, Agan, Fieberg, Hullsiek, Crum-Cianflone, Weintrob, Ganesan, Barthel, Bradley, Agan
Drafting manuscript: Chun, Landrum, Fieberg
Critical revision of the manuscript: Hullsiek, Lifson, Crum-Cianflone, Weintrob, Ganesan, Barthel, Bradley, Agan
Final approval of manuscript: Chun, Fieberg, Hullsiek, Lifson, Crum-Cianflone, Weintrob, Ganesan, Barthel, Bradley, Agan, Landrum
Obtaining funding: Landrum, Agan
Technical support: Bradley
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