Prevention and treatment of hepatitis B virus infection

University dissertation from Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Abstract: Despite 25 years of effective vaccines and availability of treatment options for 15 years, hepatitis B virus (HBV) infections continue to be a major global health problem. In Sweden, selective screening and vaccination programmes are used in defined high-risk groups such as newborns of chronic HBV carrier mothers and health care workers with risk of blood exposure. These preventive strategies need to be evaluated. Treatment of chronic HBV infections aims at inhibiting viral replication and progressive liver disease before long-term complications such as cirrhosis, hepatic failure and hepatocellular carcinoma develop. Particularly difficult to treat are patients with high viral replication. Today, the immunomodulating drug interferon-alpha (IFN-alpha) and the two antiviral drugs lamivudine and adefovir are licensed for treatment. Despite an increasing number of available drugs, more effective treatments with durable response are needed and currently different combination therapies are being evaluated. The aim of this investigation was to study some aspects of prevention and treatment of HBV infection. Study I concerned the prevention of HBV in children born to HBsAg-positive mothers during the years 1983-1989. Two of 212 children in the study became chronic carriers. The first child was born to an HBeAg-positive mother with high HBV DNA levels (probably intrauterine infection), and the other, an unvaccinated child, was infected horizontally. Additionally, eight unvaccinated children had an asymptomatic seroconversion, emphasising the need for vaccination of newborns of anti-HBepositive mothers. Most children attained long-term seroprotective anti-HBs levels. In study II alanine aminotransaminase (ALT) levels were evaluated retrospectively as a surrogate marker for HBV DNA levels in HBeAg-negative carrier mothers. Of 179 sera analysed, eight (4.5%) tested positive for HBeAg, whereas 171 (95.5 %) were HBeAg-negative. Among the HBeAg-negative mothers, nine had H13V DNA levels predefined as high (> 105 copies/mL), of whom seven had normal ALT levels, indicating low sensitivity of ALT for detecting high levels of HBV DNA. In study III the outcome and cost of low-dose intradermal (ID) hepatitis B vaccination followed by intramuscular (IM) boosters in non-responders were retrospectively analysed. Seroprotection was achieved in 1,517/1,840 (82.5%) vaccinees. Among non-responders, two-thirds had no detectable antibodies and one-third had levels of 1-9 IU/L (hypo-responders). In the group of hypo-responders, 43/46 (94%) achieved seroprotection after a single IM booster. Among those without detectable antibodies, the first IM booster induced seroprotection in 71/136 (52%). After a second booster another 31/51 (61%) attained seroprotection. Hence, after the ID series followed by one or two IM boosters a seroprotection rate of 94-97% was reached in compliant vaccinees at a cost reduction of more than 50% compared to a standard IM vaccine series. In study IV, a prospective open pilot study, the efficacy and safety of IFN-alpha treatment in children with highly replicative chronic HBV infections were investigated. Eleven children, six boys and five girls, aged 4-14 years, with genotypes A, B, C and D, participated. They were treated with IFN-alpha 5 MIU/m2 body surface area subcutaneously three times weekly for 20 weeks and followed up over a 2-year period. Response with seroconversion and HBV DNA loss in serum occurred in two children (genotypes A and D, respectively), both with pre-treatment ALT elevation. Study V, a prospective open randomised pilot study, addressed the efficacy and tolerability of lamivudine in combination with famciclovir, with and without addition of IFN-alpha, in patients with highly replicative chronic HBV infection. Four patients (2 1%) out of 19 lost HBeAg and/or developed antiHBe during the first year after treatment cessation. Two of the four responding patients relapsed during continued two-year follow-up. Thus, only 2 of 19 (10.5%) patients had durable seroconversion. The addition of IFN-alpha did not improve the seroconversion rate, and caused the well-known adverse events associated with interferon.

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