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

Disclosures
In This Article

Discussion

In our study, a substantial percentage of both HIV-infected and HIV-uninfected Romanian adolescents have serologic evidence of past or present HBV infection, despite the absence of clinical signs of hepatitis or of biochemical abnormalities. Previous studies had shown that Romania is a high endemic region for HBV infection (> 7% population prevalence for all hepatitis B markers),[5] mostly acquired in childhood by either maternal-fetal or parenteral routes. The frequency of asymptomatic hepatitis cases has important public health consequences concerning the transmission route and the effective prophylactic measures. Surveillance data collected by the Romanian Ministry of Health during 1997-1998 indicated that acute HBV infection was associated with receiving injections among children younger than 5 years.[6] In Romania, injection was and is frequently used to administer medications.[7] Shortage of infection-control supplies, including puncture-proof sharps containers, disinfecting solutions, and single-use gloves, has been identified in Romania as one possible explanation for HBV transmission in hospitals and orphanages.[8] Also, in outpatient clinics, it has been suggested that sterile equipment might have become contaminated with blood before use (eg, blood specimens were collected in open wide-mouthed vials that were handled and placed on tables where injections were prepared, needles were placed in multidose vials to serve as access ports, and finger lacerations were left uncovered before preparing or administering injections). The high endemicity level of HBV infection in Romania can be attributed to all these practices.

Significant overlap exists for risk factors for acquisition of HIV, HBV, and HCV. The epidemiology of pediatric and adolescent HIV infection in Romania is unique in that almost all cases are attributable to horizontal, nosocomial transmission of the virus, in early childhood. In our study, the rate of HBV infection was significantly greater among HIV-infected adolescents than among HIV-uninfected controls: 78.3 % vs 31.7% ( P < .0001). In addition, the coinfection with HDV in chronic HBsAg carriers was present in 5.6% of HIV-infected adolescents but in none of the HIV-uninfected controls. The HIV transmission efficiency through unsafe medical injections in Romanian orphanages was estimated at 2% to 7%; the transmission efficiency for HBV is probably about 10-fold greater.[9] The magnitude of HBV coinfection contrasts with the amplitude of intervention measures: reduction of risks factors for acquisition of blood-borne pathogens, hepatitis B vaccination, and antiretroviral therapy. The low rate of HCV infection in both groups could reflect the fact that none of the study subjects reported intravenous or intranasal drug use. However, this also implies that others risk factors for HBV acquisition may be taken into consideration. For severely immunosuppressed HIV-infected patients, close contact with HBsAg carriers might multiply the risk.[10] In our study group, many HIV-infected adolescents lived for at least some period in small group homes (8-12 children) where they may have come in close contact with HBV carriers, even if their present caretakers are efficiently vaccinated against hepatitis B. Severely immunosuppressed patients may act as "supershedders" and maintain a high rate of HBV infection in the community. This is supported by the fact that HIV/HBV-coinfected patients manifest decreased responses to the HBV vaccine. Their seroconversion rates to the recombinant 3-dose HBV vaccine were 20%, compared with 78.4% in the control group ( Table 1 ); a waning over time of protective antibody titers in HIV-infected subjects has also been reported.[11] The low efficiency of immunization in HIV/HBV- coinfected adolescents suggests that other HBV prevention strategies also must be considered, including behavioral and barrier precautions, and avoidance of sharing of personal-care items (eg, razors). It also prompts us to suggest inclusion of lamivudine in the treatment of pregnant HIV adolescents for prevention of vertical transmission of both viruses. Lamivudine can suppress HBV plasma viral load, making vertical transmission unlikely, without any effects on reproduction, fertility, or risk for birth defects.

The results of our study suggest that in HIV-infected adolescents, degree of immunosuppression is correlated with persistence of HBV replicative markers. Natural seroconversion from HBeAg to anti-HBe is associated with sustained remission of hepatitis in about two thirds of patients infected with HBV alone. The HIV/HBV- coinfected adolescents we studied showed decreased clearance rates for HBsAg and HBeAg that were related to degree of immunosuppression. This fact amplifies concerns about the possible long-term consequences of chronic HBV infection and liver disease for HIV-infected children, as well as the need for effective therapeutic strategies in the management of patients coinfected with HIV and HBV.

Reactivation to HBeAg can occur at any time. Recent follow-up data indicate that a 4% spontaneous reactivation rate occurs over 1-18 years.[12] HIV infection sometimes is associated with reactivation of HBV, accelerated loss of anti-HBs, higher levels of HBV DNA, and lower ALT levels, because of a depressed immune response.[13] When HBeAg seroconversion has been prompted by antiviral therapy, the short-term stability (6 months) of this seroconversion may be reduced.[14] Following treatment with interferon-alpha, reactivation rates between 10% and 24% are described over a similar period (> 6 months) of follow-up.[15] The data supporting the stability of lamivudine-induced seroconversion are even more varied. A reactivation rate as high as 50% has been reported in HIV/HBV- coinfected patients after withdrawal of lamivudine[16]; this may portend decreased effectiveness of anti-HBV therapy in HIV/HBV- coinfected individuals. Those who are inactive carriers (HBeAg-negative with < 105 copies/mL of HBV DNA and normal ALTs) do not need treatment, but should have periodic monitoring of ALT, aspartate aminotransferase (AST), and HBV DNA. Liver enzyme elevations due to HAART-related hepatotoxicity as well as to coinfection with HBV or HCV have been frequently reported in HIV patients.[17] However, in our study, only 19% (95% CI = 13-26.8) of samples from coinfected patients had aminotransferases level beyond the upper normal limit of 30 IU/mL, none with associated clinical signs. The highest values were always found in patients with more than 107 HBV DNA copies/mL. On the contrary, the majority of those who cleared HBeAg had undetectable viremia and normal ALT levels.

Although we did not observe it in the present study, immune reconstitution sometimes can precipitate the evolution of HBV infection, increasing the risk for progression to cirrhosis. Thus, a short-term goal of antiviral therapy in the HIV/HBV- coinfected patient is to prevent this progression to cirrhosis. Only long-term follow-up studies will indicate whether antiretroviral therapy will have the same beneficial effect on HBV transmission as it has on HIV transmission.

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