High Prevalence of Hepatitis B Virus Markers in Romanian Adolescents With Human Immunodeficiency Virus Infection

Simona Maria Ruta, MD, PhD; Rodica Floarea Matusa, MD, PhD; Camelia Sultana, MD; Loredana Manolescu, MD; Claudia A. Kozinetz, PhD; Mark W. Kline, MD; Costin Cernescu, MD, PhD

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Demographic data for HIV-infected adolescents and HIV-uninfected controls are shown in Table 1 . The 2 groups did not differ significantly by age or sex ratio. Ninety-one percent of controls, but only 70.2% of HIV-infected adolescents, reside with their own families. In Romania, universal immunization against hepatitis B of all newborns was introduced in 1995 and extended to preschool children in 1999. The history of complete anti-hepatitis B vaccination was extracted from records of children in both groups and compared with the presence of protective titers of anti-HBs antibodies at baseline. Seven out of 35 (20%) HIV-infected adolescents vaccinated against hepatitis B demonstrated seroconversion to anti-HBs antibodies, compared with 40 out of 51 (78.4%) vaccinated adolescents in the control group. The successfully vaccinated adolescents were excluded from analysis in Table 2 .

The prevalence of HBV markers was significantly greater among HIV-infected adolescents than among HIV-uninfected controls (78.3% vs 31.7%, respectively [ P < .0001]) ( Table 2 ). Subjects with HBsAg and anti-HBc total antibodies were defined as being chronic HBsAg carriers. Forty-four percent of HIV-infected adolescents vs 7.9% of controls had chronic hepatitis B ( P < .0001). Further evaluation of these individuals included HBeAg, anti-HBe, and HBV DNA to determine disease status. Eighteen (11.2%) HIV-infected adolescents and 8 (2.2%) controls were HBeAg-positive ( P < .0001), suggesting that HIV-infected adolescents have decreased rates of clearance of HBsAg and HBeAg. All subjects without HBe antigen had undetectable levels of HBV DNA, while the HBeAg presence was accompanied by high viral load values (range, 1.5-4 x 107 copies/mL). Chronic HBsAg carriers were tested for hepatitis D virus (HDV) superinfection. Nine out of 70 (12.8%) HBsAg-positive HIV-infected adolescents, but none of the controls, had anti-HDV antibodies, which confer a HDV seroprevalence rate of 5.6% in the HIV cohort.

The serologic pattern for viral clearance was defined as negative HBsAg but positive anti-HBs and anti-HBc antibodies. The difference between the proportions of HIV-infected subjects (14.3%) and controls (8.4%) who had this pattern of HBV clearance is not statistically significant. The burden of past or chronic HCV infection was low in both groups, possibly reflecting the absence of intravenous-drug use in both groups. The prevalence of anti-HCV antibody was 1.8% among HIV-infected adolescents and 0.8% among controls.

During the term of follow-up, 4 more HIV-infected adolescents (11% of the previously HBV-uninfected) became HBsAg-positive. Acute HBV infection was defined as presence of IgM anti-HBc antibody and the incidence was computed as 24.9 cases/1000 person-years. No new cases of HCV seroconversion were observed. There were 3 deaths among the HIV-infected adolescents, 2 of whom were coinfected with HBV.

The relation between HBV replicative markers and degree of immunosuppression. Most evidence supports the idea that HIV accelerates progression of HBV disease.[2,3] To understand the influence of advanced HIV disease on the evolution of HBV infection, we compared HIV-infected adolescents with severe immunosuppression (CD4+ cell count < 200 cells/mcL) vs those with moderate immunosuppression (CD4+ cell count > 200 cells/mcL). Subjects of all immunologic strata were similarly exposed to HBV, as shown by the prevalence of anti-HBc antibody, but fewer adolescents with severe immunosuppression cleared HBsAg and HBeAg. As shown in Table 3 , 59.6% of the severely immunosuppressed patients (CD4+ cell counts < 200/mcL) were HBsAg-positive compared with 34.6% of those with CD4+ cell counts > 200/mcL ( P = .02). The seroprevalence of HBeAg was more than double in AIDS patients: 17.5% vs 7.7 %. Patients with severe immunosuppression were more likely to maintain active HBV replication: 22.8% vs 5.7% ( P = .002) had high viremic samples (> 107 HBV DNA copies/mL). No correlation between the HIV viral load and the HBV DNA copies number was found.

In the absence of HIV coinfection, it is likely that most HBV carriers who are HBeAg-positive will eventually seroconvert to anti-HBe antibodies, even if untreated.[4] Clearance rates of HBsAg and HBeAg -- defined as the proportion of those who seroconvert to anti-HBs and anti-HBe antibodies, respectively, from the total number of coinfected adolescents -- after 1 year of follow-up are indicated in Table 4 . After 1 year of follow-up, 31.7% (95% confidence interval [CI] = 24.2-40.3) of all patients coinfected with HIV and HBV seroconverted to anti-HBe. However, in severely immunosuppressed coinfected patients, the proportion of those who cleared HBeAg and developed anti-HBe antibodies was substantially lower. Only 4.7% of the anti-HBc-positive patients with < 100 CD4+ cells/mcL vs 37.1% of the remainder developed anti-HBe antibodies ( P = .003). The development of anti-HBs antibody and the persistence of the protective titer (> 10 mIU/mL) was very low in patients with marked immunosuppression. The geometric mean of the anti-HBs antibodies titer was 21 mIU/mL in patients with < 100 CD4+ cells/mcL, compared with 374 mIU/mL in the rest of the coinfected patients. On 1-year follow-up, only 23 (74.2%; 95% CI = 56.5-86.5) out of the total 31 coinfected HIV/HBV-coinfected patients who cleared HBsAg maintained a protective anti-HBs antibodies titer of > 10 mIU/mL (data not shown).

Seventeen HBsAg-positive patients received 150 mg of lamivudine + 300 mg zidovudine ( Combivir ; GlaxoSmithKline; Research Triangle Park, North Carolina) twice daily, as part of their antiretroviral regimen, consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 protease inhibitor (PI). After 1 year of treatment, 4 patients (23.5%; 95% CI = 9-47.7) achieved undetectable levels of serum HBV DNA, while HBsAg loss was recorded in 7 patients (41.2%; 95% CI = 21.5-64) and sustained normalized alanine aminotransferase (ALT) was reported in 13 patients (76.5%; 95% CI = 52.2-90.9). HBeAg-positive patients did not lose this replicative marker, and seroconversion to anti-HBe antibodies was not demonstrated.

The influence of immune reconstitution on the clearance of HBsAg and HBeAg was evaluated in 57 patients who had evidence of increased level of CD4+ cells after 1 year of highly active antiretroviral therapy (HAART). A group of 5 out of 21 patients (23.8%; 95% CI = 10.2-45.4) with previous CD4+ cell count < 100 cell/mcL and another of 7 out of 28 (25%; 95% CI = 12.4-43.6) patients with CD4+ cell count < 200 cells/mcL improved their immunologic status, achieving levels of > 500 CD4+ cells/mcL. Four patients in the first group and 3 in the second cleared the HBsAg, but none the HBeAg.


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