Efficacy of pegylated interferon alpha-2b for the treatment of chronic delta hepatitis in a patient co-infected with HIV

Abstract

A 26-year-old woman from Cameroon, infected with HIV-1, was referred to our unit for the exploration of liver function test abnormalities. In October 2001, she had been treated for one year with zidovudine, didanosine and efavirenz. On admission, immunovirological markers showed a CD4 cell count of 350 cells/μl and an undetectable HIV-RNA level. Liver function tests were as follows: alanine aminotransferase 68 IU/l (normal 0–53), aspartate aminotransferase 69 IU/l (normal 0–36), bilirubinemia 6 μmol/l (normal 1–17), γ-glutamyl transferase 41 IU/l (normal 10–32) and alkaline phosphatase 50 IU/l (normal 23–85). Albuminemia was 40 g/l (normal 35–45). The prothrombin time had increased to 17.5 s (normal 12.4; 42%), V factor was at 50%. Liver ultrasound showed a normal liver without hepatic dysmorphology. Serology for hepatitis C was negative, and hepatitis C virus RNA was undetectable using a polymerase chain reaction (PCR) assay. Hepatitis B surface (HBs) antigen was positive. Hepatitis B e antigen was negative, and anti-hepatitis B e antibody was positive. Hepatitis B virus (HBV) DNA was present at a high level (higher than 106 copies/ml, Roche COBAS Amplicor monitor; Roche Diagnostics, Pleasanton, California, USA). Anti-hepatitis D virus (HDV) antibodies were positive (enzyme immunoassay Sorin total antibodies), and HDV RNA using a reverse transcriptase PCR assay (threshold of detection 1000 copies/ml) was also positive, leading to the diagnosis of chronic hepatitis D. A liver biopsy showed a precirrhotic stage, classified A3F3 according to the metavir score. The patient was first treated with lamivudine at 100 mg per day. Lamivudine was associated with zidovudine and efavirenz, and didanosine was discontinued. After 3 months of lamivudine treatment, HBV DNA was undetectable using a branched DNA assay (threshold of detection 0.7 × 106 eq.genome/ml). PCR HDV was still positive. The prothrombin time improved to 16.5 s (normal 12.4; 60%), allowing us to start a treatment using pegylated IFN α-2b, at the regimen of 1.5 μg/kg a week administered subcutaneously. This treatment was stopped after 18 months even though HBs antigen was still positive, as a result of the increase in severe asthenia. At the end of pegylated IFN treatment, HBV DNA and HDV RNA were both undetectable using PCR assays. Liver function tests were normal and prothrombin time was 14.3 s (normal 12.4; 74%). During the pegylated IFN treatment, the CD4 cell count dropped to 270 cells/μl, as did the white blood cell count to 2100. The HIV-RNA level was still undetectable. No anaemia or thrombopenia were observed. Thirty-eight weeks after the end of treatment, HBV DNA and HDV RNA were still undetectable using PCR assays. The CD4 cell count went up again to 412 cells/μl (34.5%). However, no HBs seroconversion was observed during the follow-up. HDV is an enveloped, spherical particle with an RNA genome [1]. This virus requires a helper function provided by HBV for replication. It causes severe and rapidly progressive liver disease, leading to cirrhosis and hepatocellular carcinoma. High doses of standard IFN are currently the only effective treatment for chronic HDV [2,3]. In a series reported by Farci et al. [4], the biochemical and virological response rates were 71 and 50%, respectively, at the end of a 48-week treatment with a high dose of IFN α-2b (9 million units thrice weekly). The duration of treatment is not well codified, and IFN treatment is usually carried out until antigen HBs seroconversion is observed [5]. With regard to patients co-infected with HIV and HDV, Puoti et al. [6] treated 16 HIV-infected patients with chronic hepatitis D with standard IFN α-2b. The patients received 10 million units thrice weekly for 6 months, then 6 million thrice weekly for an additional 6 months, and a one-year course of 3 million units thrice weekly if alanine aminotransferase activity values decreased by at least 50% from basal levels. Two years after the discontinuation of IFN treatment, only one patient showed a complete biochemical, virological and histological response. We decided to treat the patient with pegylated IFN because pegylated IFN has proved to be more effective in the treatment of chronic hepatitis C and recently also in chronic hepatitis B, compared with standard IFN [7–9]. It is important to note that the clinical and biological tolerance of pegylated IFN were good. The only side-effects were asthenia and a moderate decrease in the CD4 cell count related to pegylated-IFN-induced leukopenia. As far as we know, this is the first case of the use of pegylated IFN in the treatment of chronic hepatitis D in an HIV-1-co-infected patient. Further studies using pegylated IFN for chronic hepatitis D should be carried out to confirm the efficacy of this treatment.