Fw: NATAP: Peg/RBV Treats HBV/HCV Coinfected Patient
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Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-Î±2b plus ribavirin treatment in a patient with hepatitis B and C coinfection
European Journal of Gastroenterology & Hepatology: Volume 18(9) September 2006 pp 1019-1022
Rautou, Pierre-Emmanuel; Asselah, Tarik; Saadoun, David; Martinot, MichÃ¨le; Valla, Dominique; Marcellin, Patrick
Service d'HÃ©patologie and INSERM CRB3, University of Paris VII, HÃ´pital Beaujon, Clichy, France
In hepatitis B or hepatitis C endemic areas, the number of patients with dual infections is substantial. In such patients, interferon-Î± plus ribavirin can achieve sustained hepatitis C virus (HCV) clearance and hepatitis B e antigen (HBeAg) seroconversion. Pegylated interferon (PegIFN), an established treatment for hepatitis C, is currently increasingly recognized as an efficient therapy for hepatitis B. No case of successful use of PegIFN plus ribavirin has yet been reported, however, in hepatitis B virus (HBV) and HCV coinfection.
We report on a 32-year-old man, of Kampuchean origin, with chronic hepatitis B, as documented by the presence of hepatitis B surface antigen with HBeAg, who was coinfected with HCV genotype 1. On therapy with PegIFN-Î±2b plus ribavirin, HCV RNA became undetectable at week 17. At the end of the 48 weeks of treatment, HCV RNA was still undetectable, HBV DNA was reduced and HBeAg remained positive. Twelve weeks after the end of treatment, HBV DNA reduction was followed by HBeAg to anti-HBe seroconversion. Two years after the end of treatment, HCV RNA and HBV DNA were still undetectable, and HBeAg to anti-HBe seroconversion was maintained. We conclude that the combination of PegIFN plus ribavirin may induce suppression of both viral infections.
It is estimated that there are approximately 400 million hepatitis B virus (HBV) carriers and 170 million hepatitis C virus (HCV) carriers worldwide. In hepatitis B or hepatitis C endemic areas such as Asia or sub-Saharan Africa, the number of patients with HBV and HCV coinfections is substantial. In Taiwan, for example, antibody to HCV was present in 11% of patients with HBV-related chronic liver diseases . Moreover, HBV-HCV coinfection seems to increase the risk of developing cirrhosis or hepatocellular carcinoma . A recent study  reported the use of conventional interferon plus ribavirin, in 21 patients with HBV-HCV coinfection. No case of treatment with pegylated interferon (PegIFN) plus ribavirin, however, has yet been reported. We report a case of successful use of this treatment, since our patient eradicated HCV and seroconverted from hepatitis B e antigen (HBeAg) to the antibody to hepatitis B e antigen (anti-HBe).
In October 2002, a 32-year-old man, born in Kampuchea, was referred for chronic HBV-HCV coinfection. He had no history of intravenous drug use, no alcohol consumption and was not receiving any medication. Physical examination revealed no abnormality. The patient weighed 56 kg and was 1.69 m tall. Laboratory tests showed an alanine aminotransferase (ALT) level of 53 IU/l (normal range <40 IU/l). The presence of antibodies against HCV was detected with a third-generation enzyme-linked immunosorbent assay (Ortho HCV 3.0 ELISA test system; Ortho-Clinical Diagnostics, Germany). Serum HCV RNA was detected using a reverse transcription-polymerase chain reaction (RT-PCR) (Cobas Amplicor HCV Monitor Version 2.0; Roche Diagnostic, Neuilly-sur-Seine, France) with a sensitivity of 100 copies/ml. HCV genotyping performed in the 5â?²-noncoding region of the genome using reverse hybridization with the line probe assay (Lightcycler; Roche) revealed a HCV genotype 1 infection. Serum hepatitis B surface antigen (HBsAg) was positive, antibody to hepatitis B surface antigen (anti-HBs) was negative, antibody to hepatitis B core antigen was positive, serum HBeAg was positive, and anti-HBe was negative. These HBV serological markers were analysed by enzyme immunoassay (MEIA; Abott, USA). Serum HBV DNA level was 71Ã-103 copies/ml (bDNA Assay; Bayer, USA). Antibodies against hepatitis delta virus were negative. There was no marker of human immunodeficiency virus infection and no autoimmune antibodies.
A liver biopsy was performed and histological examination revealed portal fibrosis with rare septa (Metavir score F2) and a moderate activity (Metavir score A2).
>From March 2003, the patient received PegIFN-Î±2b 1.5 Î¼g/kg per week (Viraferon-Peg; Schering Corp., USA) plus ribavirin 800 mg/day (Rebetol; Schering Corp) (Fig. 1). In July 2003, because of weight loss, anorexia and fatigue, the PegIFN dose was decreased to 1 Î¼g/kg per week, maintaining the same dose of ribavirin. This treatment was continued until February 2004 (the total duration of treatment was 48 weeks).After 17 weeks of treatment, HCV RNA became undetectable by RT-PCR assay, with a sensitivity of 100 copies/ml. On the five following samples, HCV RNA was still undetectable with transcription-mediated amplification assay (TMA, Versant TM HCV RNA; Bayer Diagnostics), with a sensitivity of 50 copies/ml. At the same time, the HBV DNA level increased to 1180 Ã-103 copies/ml by PCR assay (Amplicor HBV Monitor, COBAS; Roche), and subsequently reached 100 Ã-106 copies/ml at week 22. At the end of the treatment, HCV RNA remained undetectable, and HBeAg was still positive and anti-HBe negative. Twelve weeks after the end of treatment, HCV RNA remained undetectable and HBV DNA decreased to 442 copies/ml by RT-PCR (RT-PCR, COBAS TaqMan; Roche). At the same time, we observed the loss of HBeAg, and the detection of anti-HBe and of anti-HBs temporarily (83 mIU/ml by MEIA). Anti-HBs again became negative.
Two years after the end of PegIFN plus ribavirin, HCV RNA remained undetectable (TMA, Versant TM HCV RNA; Bayer Diagnostics), and HBV DNA (with a sensitivity of 170 copies/ml; RT-PCR, COBAS TaqMan; Roche) was also undetectable, HBeAg was still negative, anti-HBe was still positive, and HBsAg was still positive.
Our patient had HBV-HCV coinfection. He might have acquired HBV infection in childhood, as he came from a hepatitis B endemic area. Several clinical studies reported that replication of both HBV and HCV  decreases in cases of coinfection with these viruses, indicating mutual interference. Moreover, some studies have shown that HBV replication is most affected, suggesting that HCV plays a dominant role . This is in accordance with the findings of Shih et al. , who described a reduced expression of HBV transcripts in the presence of HCV structural genes in Huh-7 cells.
Treatment with PegIFN plus ribavirin during 48 weeks achieved HCV clearance. HCV RNA remained undetectable, using a highly sensitive PCR, 40 weeks after the end of the treatment. In patients with HBV-HCV coinfection receiving interferon monotherapy, response rates have been low. For example, out of 16 patients treated with 9 million U three times weekly for 6 months, only five (31%) developed a sustained response . In a recent open label nonrandomized study , IFN-Î±2a plus ribavirin during 24 weeks was evaluated in 21 patients positive for both serum anti-HCV and HBsAg: 57% were HCV genotype 1 and 43% were HCV genotype 2. They were compared with 30 HCV monoinfected patients: 67% were HCV genotype 1 and 33% were HCV genotype 2. Serum HCV RNA was still undetectable 24 weeks after the end of the treatment in nine out of the 21 (43%) HBV-HCV coinfected patients, which was similar to the 30 HCV monoinfected controls (60%, P=0.63). PegIFN-Î±2a  and PegIFN-Î±2b plus ribavirin , however, have yielded higher sustained virological response rates as compared with conventional IFN-Î± plus ribavirin in all HCV monoinfected patients (about 55% and 46%, respectively) and in HCV genotype 1 (about 44% and 34%, respectively). The association of PegIFN plus ribavirin is now considered the optimal therapy for chronic hepatitis .
Our patient was infected with HCV genotype 1, which is associated with a lower sustained virological response rate than other genotypes. Yet certain predictors of sustained virological response were present: he was young, had no bridging fibrosis, and had a low body weight . In addition, compliance was good since he received more than 80% of PegIFN-Î±2b and a full ribavirin dosage for the expected duration of therapy .
Regarding HBV infection, 40 weeks after the end of PegIFN plus ribavirin, HBV DNA remained undetectable with a high-sensitivity PCR, HBeAg was still negative and anti-HBe was positive. The current consensus guidelines on hepatitis B recommend the use of IFN-Î± as the first-line therapy and of nucleoside or nucleotide analogues as the second-line therapy . Two recent studies, however, have shown the interest of PegIFN-Î±2a alone in patients with HBeAg-positive  and HBeAg-negative  chronic hepatitis B. In the first study, the combined response rate (HBeAg loss, HBV DNA suppression defined as <500 000 copies/ml, and ALT normalization) was 24% and HBeAb seroconversion was 32% with PegIFN-Î±2a, versus 12% (P=0.036) and 25% (P=0.185), respectively, with conventional IFN-Î±2a. In the second study, the rate of sustained suppression of HBV DNA to below 400 copies/ml was 19% with PegIFN-Î±2a monotherapy. Indeed, if PegIFN-Î±, like conventional IFN-Î±, has a dual immunomodulatory and antiviral mode of action , the pegylation increases the half-life and improves the pharmacokinetics of the protein . In HBV-HCV coinfected patients treated with a combination of interferon and ribavirin, a disappearance of serum HBV DNA (with a detection limit of 200 copies/ml) was obtained in 35% of the hepatitis B viremic patients 24 weeks after the end of the treatment, but was not accompanied by loss of HBsAg. Among these 21 HBV-HCV coinfected patients, only three were positive for HBeAg. All these three patients lost HBeAg after treatment, and one seroconverted to anti-HBe .
In our case, before the beginning of the treatment, the likelihood of response to IFN-Î± was low because the patient had a pretreatment ALT level lower than 1.5 times the upper limit of normal . This predicting factor, shown with IFN-Î±, is also valid with PegIFN . Yet, the ALT flare, which appeared after 17 weeks of treatment, is a known predictor of good response in patients with HBeAg-positive chronic hepatitis treated with IFN-Î± . This seems to be also true in patients treated with PegIFN, since there is a significant association between ALT flares during therapy and normalization of ALT levels 24 weeks after the end of the treatment .
Twelve weeks after the treatment, anti-HBs appeared temporarily while HBsAg persisted. The human humoral immune response to HBV is mainly directed against a conformational antigen of the envelope of the virus, common to all HBsAg subtypes. This important antigen, the group 'a' determinant, results in the covalent assembly of two subunits of the major S protein , and the immune response it produces in man is clearly recognized as protective. Concurrent HBsAg and anti-HBs in acute and chronic hepatitis B has been noted as a common serological finding since 1987 [17,18]. HBV escape mutants with mutations in the S gene affecting the expression of group-specific determinants would survive in some carriers after they seroconvert to antibody against surface antigen. In such mutants, anti-HBs can bind group 'a' antigen but do not neutralize it.
During the treatment, at week 17, both ALT and HBV DNA levels increased. We can distinguish three phases in this phenomenon. The first phase, after few weeks of treatment with PegIFN plus ribavirin, consisted of HCV RNA clearance. This suppression happened first probably because HCV replication was dominant. During the second phase, HBV replication, which was inhibited by HCV , was reactivated and the HBV DNA level increased. During the third phase, we observed an ALT flare corresponding to an exacerbation of the immune response against HBV, as is seen in HBV monotherapy cases. After the end of the 48 weeks of treatment, this reactivation was followed first by normalization of the ALT level, and then by HBeAg to anti-HBe seroconversion and by a decreased level of serum HBV DNA corresponding to HBV suppression.
In conclusion, our patient had an HBV-HCV coinfection. We treated him for 48 weeks with PegIFN-Î±2b plus ribavirin, since PegIFN is more effective than conventional interferon in both HBV and HCV chronic hepatitis [6,7,11,12]. This treatment was associated with HCV clearance, HBeAg to anti-HBe seroconversion, despite several predictive factors of nonresponse: for HCV, the genotype 1; and for HBV, the low pre-treatment ALT level. Our case illustrates the efficacy of PegIFN plus ribavirin on both HCV and HBV in HBV-HCV coinfected patients. Randomized controlled trials are needed to determine whether this combination is more effective than the combination of conventional IFN-Î± plus ribavirin.
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