Loss Of Hepatitis B Virus DNA Research Articles

XVIII Latin American Congress

XVIII Latin American Congress

Think Twice If You Consider Entecavir Treatment in Cases with Lamivudine Refractoriness

We read with interest the article by Shim et al.1 concerning the efficacy of entecavir (ETV) in patients with chronic hepatitis B resistant to both lamivudine (LAM) and adeofovir (ADV) or to LAM alone. In this study, they indicated that ETV given at 1 mg/day for 48 weeks resulted in lesser hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) reduction in the LAM/ADV-resistant group than compared with the LAM-resistant group. They also noted that HBV DNA loss was significantly higher in the LAM-resistant group compared with the LAM/ADV-resistant group (34% versus 10%). However, they showed that virological breakthrough was similar in both groups. They also underlined that virological response at 12 weeks determined the degree of HBV DNA reduction over 48 weeks of therapy, regardless of previous antiviral treatment. In their study, Shim et al. underlined the importance of multidrug resistance in cases with inappropriate use of antivirals in HBV infection. The same authors suggested, in the introduction section, that “in terms of salvage therapy for LAM-resistant or ADV-resistant chronic hepatitis B infection, the American Association for the Study of Liver Diseases (AASLD) practice guideline recommended switching to ETV” monotherapy as an optimal strategy. However, according to the current guidelines, including AASLD 2009,2 European Association for the Study of the Liver 2009,3 and Asian Pacific Association for the Study of the Liver 2008,4 what the authors did seemed to be inappropriate to suggest to the readers. The guidelines mentioned above unanimously indicated that ETV can be recommended as a rescue therapy only for ADV-resistant chronic HBV infection having Asp236-to-Thr236 (N236T) and/or Ala181-to-Thr181/Val181 (A181T/V) substitutions. Contrary to what the authors wrote in the introduction section of their article, AASLD guidelines in 20092 on HBV infection clearly indicate that ETV is not an optimal treatment for LAM-refractory HBV. It is clearly known that Leu180-to-Met180 (L180M) + Met204-to-Val204 (M204V) and L180M + M204V + Asn236-to-Thr236 (N236T) mutants behaved 6.25-fold resistant to ETV compared with wild-type HBV.5 We also know that genotypic resistance to ETV will develop at a rate of 43% at the end of 4 years.6 Expectedly, two patients in the series of Shim et al.1 developed virological breakthrough with Ser202-to-Gly202 (S202G) ETV resistance substitutions at 36 weeks of treatment, and one patient developed biochemical breakthrough in the LAM-resistant group of patients. Unfortunately, the readers were not informed in this article how the authors treated these two cases in their series. Another relevant article in this field showed that although HBV DNA suppression was achieved in a higher percentage of patients, there was an emergence of nearly 8% resistance to ETV monotherapy in cases with previous LAM resistance in year 2.7 Thus, this strategy led to selection of multidrug-resistant HBV strains with maximal viral resistance in the near future. Another concern with this article is that the authors also underlined the impact of 1 log HBV DNA reduction at 12 weeks on antiviral efficacy at 48 weeks. However, it would be more valuable if they could provide us with the threshold level of HBV DNA reduction at 12 weeks to achieve HBV undetectability in their cases. As a result, the authors in this article1 tested an approach which is absolutely not valid and nor practical at present. Currently, we believe that ETV monotherapy is not a good alternative as a rescue therapy for cases with LAM and or LAM/ADV resistance, whereas continued treatment resulted in virus suppression in a higher percentage of patients in the series of Shim and colleagues. ETV is obviously not a drug with a high genetic barrier to resistance in the setting of LAM refractoriness. In such situations, we have to admit the effectiveness of other alternative drugs, including tenofovir. Yucel Ustundag*, Omer Topalak , * Zonguldak Karaelmas University School of Medicine, Department of Internal Medicine, Gastroenterology Clinics, Zonguldak, Turkey, Dokuz Eylül University School of Medicine, Department of Internal Medicine, Gastroenterology Clinics, Izmir, Turkey.

Predictors of Response to Lamivudine Treatment in Children with Chronic Hepatitis B

Lamivudine, an oral nucleoside analogue, is a potent inhibitor of hepatitis B virus (HBV) replication. The decision to initiate therapy should be based on variables which are predictive of lamivudine-induced HBeAg loss. The aim of this study was to identify the predictive factors of responsiveness to lamivudine treatment in children with chronic hepatitis B. Lamivudine, 3 mg/kg/day (maximum, 100 mg/day), was given to 39 children with chronic HBV infection for more than 6 months. We retrospectively analyzed the effects of baseline factors on virologic response, which was defined as the loss of HBeAg and HBV DNA after cessation of therapy. Univariate and multivariate analyses examined the effects of lamivudine treatment, age, gender, duration of treatment, previous interferon therapy, maternal HBsAg state, baseline alanine aminotransferase (ALT) and HBV DNA level. Serum HBeAg and HBV DNA became negative in 20 (51.3%) out of 39 children at the time of cessation of lamivudine treatment. In the univariate analysis, higher baseline ALT and lower HBV DNA level were independently associated with a favorable response to lamivudine treatment (p<0.05). Multivariate regression analysis showed that elevated baseline ALT was the best independent predictor of response to lamivudine treatment (p<0.05). Virologic response of lamivudine could be expected in the half of children with chronic HBV infection. Children with elevated pretreatment ALT levels were most likely to respond to lamivudine treatment.

Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: A meta-analysis

Chronic hepatitis B virus (HBV) infection is a serious problem because of its worldwide distribution and possible adverse sequelae, such as cirrhosis and hepatocellular carcinoma. Thymosin alpha-1 (Talpha1) is an immune modifier that has been shown to be effective for chronic hepatitis B (CHB) in some trials. But the trials comparing Talpha1 vs. interferon alpha (IFNalpha) treatment in CHB have been small and the results have been inconsistent. So we conducted a meta-analysis to compare the efficacy of Talpha1 and IFNalpha in the treatment of CHB. Generally, four randomized controlled trials including 199 CHB patients who received Talpha1 or IFNalpha treatment were identified through MEDLINE and EMBASE online search. Virological (for hepatitis B e antigen (HBeAg) positive patients, loss of HBV DNA and HBeAg; for HBeAg negative patients, loss of HBV DNA), biochemical (normalization of transaminases) and complete responses (fulfill criteria of biochemical and virological response simultaneously) were analyzed using the intention-to-treat method. The odds ratio (OR) was used to measure the magnitude of the efficacy. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of 6 months treatment were 0.62 (0.35, 1.10), 0.60 (0.34, 1.05) and 0.54 (0.30, 0.97), respectively. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of follow-up (6 months post-treatment) were 3.71 (2.05, 6.71), 3.12 (1.74, 5.62) and 2.69 (1.47, 4.91), respectively. These data showed that compared with IFNalpha, the benefit of Talpha1 was not immediately significant at the end of therapy, but virological, biochemical and complete response had a tendency to increase or accumulate gradually after the therapy. For three of the four trials that studied HBeAg-negative patients, the results are mostly applicable to HBeAg-negative CHB.

Sequential Combination Therapy for Chronic Hepatitis B: More Challenges to Be Tackled

TO THE EDITOR: We read with great interest the article entitled Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis by Sarin et al. in the January 2007 issue (1). Currently, six agents have been approved for the treatment of chronic hepatitis B virus (HBV) infection, a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide (2). However, the short-term efficacy of each agent alone or even simultaneous combinations of different agents remains unsatisfactory for both HBeAg-positive and -negative patients (3); it is thus key to identify new strategy to improve the rate of therapeutic response in chronic hepatitis B patients. In this article, the authors compared two treatment strategies in HBeAg-positive patients: 27 received placebo for 4 wk followed by PEG-IFN for the next 24 wk as group A, and 36 received lamivudine for 4 wk followed by PEG-IFN for the next 24 wk as group B. They found that at week 52, that is, 24 wk after the end of treatment, a higher percentage of patients in group B had undetectable serum HBV DNA (50% vs 15%, P = 0.028) and HBeAg loss (39% vs 15% P = 0.005) compared with group A. They therefore suggested that sequential combination therapy of initial direct antivirals before using immunomodulators may improve sustained responses in HBeAg-positive patients. Although their findings seem helpful to practicing physicians, several critical points need to be addressed before drawing definite conclusions.

Efficacy of adefovir dipivoxil in the treatment of lamivudine‐resistant hepatitis B virus genotype C infection

Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.

Hepatitis B Virus: Something Old, Something New

Hepatitis B Virus: Something Old, Something New

Patients with and without loss of hepatitis B virus DNA after hepatitis B e antigen seroconversion have different virological characteristics

The characteristic differences between patients with and without loss of hepatitis B virus (HBV) DNA after achieving hepatitis B e antigen seroconversion were analyzed by comparing changes in HBV DNA and HBV core-related antigen levels during a period from 3 years before to 3 years after the seroconversion. Of the 24 seroconverters, 6 (inactive replication group) showed continuous loss of HBV DNA in serum after the seroconversion and the remaining 18 did not lose HBV DNA (active replication group). The HBV DNA level was similar between the two groups, while the HBV core-related antigen level was significantly lower in the active replication group than in the inactive replication group before the seroconversion. The levels of both HBV DNA and HBV core-related antigen decreased remarkably around the time of seroconversion in the inactive replication group, while these levels did not change or decreased slightly in the active replication group. After the seroconversion, the HBV DNA level was significantly higher in the active replication group than in the inactive replication group, while the HBV core-related antigen level was similarly low between the two groups. Because the serum level of HBV core-related antigen mainly reflects that of HBe antigen, the low level of HBV core-related antigen seen after seroconversion in both groups might have contributed to the occurrence of seroconversion. The precore and core promoter mutations which cause diminished excretion of hepatitis B e antigen were significantly more frequent in the active replication group than in the inactive replication group. It was therefore considered that the seroconversion was caused mainly by a decrease in viral replication in the inactive replication group, and mainly by a decrease in HBe antigen production in the active replication group.

Higher Efficacy of Sequential Therapy with Interferon-alpha and Lamivudine Combination Compared to Lamivudine Monotherapy in HBeAg Positive Chronic Hepatitis B Patients

Monotherapy with interferon (IFN) or lamivudine is effective in a limited proportion of chronic hepatitis B (CHB) patients. A sequential combination may have better therapeutic effects by sustained viral suppression combined with immunomodulation. To compare the efficacy of sequential lamivudine and IFN therapy versus lamivudine monotherapy in HBeAg positive CHB patients. Seventy-five treatment naïve HBeAg positive patients with histologically proven CHB and alanine aminotransferase (ALT) >1.5 x ULN received lamivudine 100 mg per day for 52 wks with IFN 5 MIU per day added for 16 wks after the first 8 wks (group A, n = 38; age 30 +/- 12 yr; M:F = 35:3) or lamivudine 100 mg per day for 52 wks (group B, n = 37; age 30 +/- 16 yr; M:F = 31:6). Biochemical and virologic responses were assessed at weeks 52 and 76 and analysis was done on intention-to-treat. Serial samples were studied for the emergence of lamivudine-resistant YM552I/VDD mutations by direct sequencing. At week 52, HBeAg loss occurred in 15 (39.5%) in group A and 14 (37.8%) in group B (p= 1.00). HBeAg loss, anti-HBe appearance, and undetectable DNA levels were seen in 26.3% and 13.5% (p= 0.249), respectively. Nine of 10 (90%) patients in group A and 1 of 5 (20%) in group B maintained the response through week 76 (p= 0.017). At week 76, 5 additional patients in group A and 3 in group B further achieved the primary end point and the overall HBeAg loss was observed in 44.7% and 18.9% (p= 0.025) and HBeAg loss, anti-HBe appearance, and undetectable hepatitis B virus (HBV) DNA levels in 36.8% and 10.8% in group A and group B, respectively (p= 0.026). At week 76, undetectable HBV DNA was seen in 39.5% and 16.2% in groups A and B, respectively (p= 0.039). Normal ALT was seen in 47.7% and 40.5% at week 52 (p= 0.489) and ALT was normal in 39.5% and 13.5% at week 76 (p= 0.018) in groups A and B, respectively. YM552I/VDD-resistant mutants emerged in 6 of 38 (15.5%) patients in group A, and 3 of 37 (8.1%) in group B (p= ns). The rate of histological improvement was comparable in the two groups. Our results demonstrate that sequential therapy is superior to lamivudine monotherapy in achieving sustained seroconversion, ALT normalization, and HBV DNA loss. Compared to 80% with sequential therapy, only 20% Indian patients with CHB did not relapse after stopping lamivudine monotherapy.

A Randomized, Controlled, Clinical Study of Thymosin Alpha-1 Versus Interferon-Alpha in Chinese Patients with Chronic Hepatitis B Lacking Hepatitis B Envelope Antigen

This study was designed to compare the efficacy and safety of thymosin-alphal (T-alpha1) with that of interferon-alpha (IFN-alpha) in patients with chronic hepatitis B who were positive for hepatitis B virus (HBV) DNA and hepatitis B envelope antibody (anti-HBe). Fifty-six patients were randomly divided into groups A and B. Both groups were comparable (p > 0.05) at baseline regarding age, sex, and alanine aminotransferase (ALT) levels. Group A patients received T-alpha1 1.6 mg subcutaneously twice weekly, while group B patients received IFN-alpha 5 million IU daily for 15 days, then thrice weekly for 6 months. Results from the 2 groups were compared with data from a group of 30 patients never treated with IFN-alpha and who were followed-up for 12 months (historical control [HC] group); the 3 groups were comparable (p > 0.05). After treatment, a complete response (ALT normalization and HBV DNA loss) occurred in 8 of 26 patients in group A (30.8%) and 14 of 30 in group B (46.7%; chi2 = 1.476, p = 0.224). After a follow-up period of 6 months, a complete response was observed in 11 of 26 patients in group A (42.3%) and 7 of 30 in group B (23.3%; chi2 = 2.299, p = 0.129). The rate of complete response was significantly greater in the IFN-alpha than HC group at the end of therapy (46.7% vs 3.3%; chi2 = 15.022, p = 0.0001), and in the T-alphal than HC group at the end of follow-up (42.3% vs 3.3%; chi2 = 12.566, p = 0.0001). Ten of the 12 T-alphal responders (i.e. partial responders; 83.3%) experienced sustained, non-detectable HBV DNA after 6 months' treatment; 6 of the 14 T-alphal non-responders (42.9%) showed a delayed response of non-detectable HBV DNA during the follow-up period. Corresponding values for group B patients were 50% (9/18) and 0% (0/12). The rate of delayed response was significantly higher in group A than the other 2 groups (chi2 = 6.686, p = 0.010; chi2 = 4.964, p = 0.038), whereas the rate of flare was higher in group B than in the other 2 groups (chi2 = 3.445, p = 0.063; chi2 = 7.668, p = 0.006), during the follow-up period. Unlike IFN-alpha, T-alphal was well tolerated, i.e. no adverse effects were noted in group A. These results suggest that a 6-month course of T-alpha1 therapy is effective and safe in patients with anti-HBe-positive chronic hepatitis B; T-alpha1 can reduce HBV replication in such patients. Compared with IFN-alpha, T-alpha1 is better tolerated and seems to induce a gradual and more sustained normalization of ALT and loss of HBV DNA. Combination therapy with T-alpha1 and IFN-alpha or nucleoside analogs for hepatitis B warrants further study.

Advances in immunomodulating therapy of HBV infection.

Patients with chronic hepatitis B virus (HBV) infection have a higher risk of developing liver cirrhosis and hepatocellular carcinoma. Interferon-alpha, lamivudine and adefovir dipivoxil are the three approved treatment for chronic HBV infection and offers the only means of preventing the development of these complications. However, the efficacy of these agents, in terms of loss of Hepatitis B e antigen with or without seroconversion to Hepatitis B e antibody, normalization of serum alanine transaminase levels, loss of serum HBV DNA, and improvement in liver histology can only be achieved in 20-30% of those treated. Long-term treatment with either lamivudine or adefovir dipivoxil can result in the development of drug resistant mutants leading to an increased length of treatment with additional nucleoside analogues. These limitations of the current antiviral therapies underline the need for alternative therapies. Specific and nonspecific immunotherapeutic strategies to restore effective virus-specific T cell responses in those with chronic HBV infection offers an interesting alternative approach. These immunotherapeutic therapies include the adoptive transfer of HBV immunity, pegylated interferon and therapeutic vaccine therapies.

Beneficial effects of ‘lamivudine pulse’ therapy in HBeAg‐positive patients with normal ALT*

Currently no therapy is given to patients with chronic hepatitis B virus (HBV) infection who are HBeAg positive with normal alanine aminotransferase (ALT) levels. Steroid priming has been shown to enhance T-helper-1 (Th-1) cell response. Lamivudine may restore immunologic competence against HBV by causing a sudden decline in the level of the virus. We examined the efficacy of lamivudine pulse therapy on the seroconversion from HBeAg to anti-HBe. This was a prospective single-blinded trial including 27 patients with chronic hepatitis B, HBeAg positive with ALT < or =1.5 times upper limit of normal (ULN). Lamivudine was administered initially for 4 weeks, then stopped for 2 weeks and later restarted and continued till 3 months after seroconversion or completion of 2 years of therapy. Twenty-six patients completed the study. Lamivudine withdrawal led to a rise in ALT levels above the ULN in 11 (42.3%) patients at 6 weeks; seven of them (63.6%) lost HBeAg compared with only two of the 15 patients (13.3%), in whom ALT levels did not rise (P = 0.011). As one patient showed a relapse, a total of eight (31%) patients responded to lamivudine pulse therapy over a mean period of 17.3 +/- 4.5 months. Responders had a higher serum albumin (P < 0.05), a lower fibrosis score (P < 0.05), and a relatively high baseline serum ALT levels (P = 0.024) than the nonresponders. YMDD mutations developed in three patients and none responded. No patient developed hepatic decompensation. Hence lamivudine pulse therapy has potential in converting HBeAg-positive, 'not-treat-worthy' (ALT < 1.5 ULN) patients to treat-worthy (ALT > 1.5 ULN) in 42%, with sustained HBeAg and HBV DNA loss in 31% patients. The effects are possibly because of a combination of antiviral and immunomodulating activities of lamivudine.

New options in the treatment of chronic hepatitis.

The short-term aim of chronic hepatitis B treatment is the suppression of Hepatitis B Virus (HBV) replication, as shown by the loss of HBV DNA by DNA hybridization and the loss of Hepatitis B e Antigen (HBeAg). Loss of Hepatitis B s Antigen (HBsAg) and HBV DNA as assayed by Polymerase Chain Reaction (PCR) is very difficult to achieve. There are two important treatment approaches. The first is immunomodulation, comprising Interferon (IFN) and other cytokine treatment and therapeutic vaccination. The second is antiviral treatment, which mainly includes treatment with nucleoside analogs. There are many limitations to IFN treatment, because it has succeeded only in a small number of patients with a high level of transaminase and a low level of HBV DNA. The theoretical basis of therapeutic vaccination is the use of a vaccine that contains epitopes known to stimulate Human Leucocyte Antigen (HLA)-restricted cytotoxic T cell activity in order to lyse the HBV-infected hepatocytes. Several strategies of hepatitis vaccination are the incorporation of both pre-S and S antigen, the incorporation of a Cytotoxic T Lymphocyte (CTL)-specific antigen, the use of an HBV vaccine complexed to Hepatitis B Immune Globulin (HBIG), and DNA vaccination. One of the limitations of therapeutic vaccination is the short duration of immunity to the CTL antigen. Lamivudine is an oral nucleoside analog with potent antiviral action. It rapidly reduces the HBV DNA level, a level that soon returns to pretreatment level after drug administration is terminated. This drug does not affect the covalently bond closed circular (ccc)DNA of infected hepatocytes; it only inhibits the formation of new viruses. One-year of Lamivudine treatment significantly improved necroinflammation and reduced the progression of fibrosis and the histologic activity index. HBeAg seroconversion occurred after prolonged treatment. The emergence of a tyrosine-methionine asparagine aspargine YMDD mutant is one of the drawbacks of lamivudine treatment. Therefore a combination with other antiviral agents or immune modulators, such as therapeutic vaccination, is likely to be more effective.

Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: Is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?

During interferon treatment of chronic hepatitis B, an alanine aminotransferase (ALT) flare may herald a sustained loss of viral replication, but the relationship between virologic response, the extent of a flare, and pretreatment hepatitis B virus (HBV) DNA level has not been defined. We retrospectively examined the impact of an ALT flare on sustained virologic response in 121 interferon-treated patients and 42 untreated controls with either low-level (<100 pg/mL) or high-level (≥100 pg/mL) viremia. The degree of ALT flare was classified as mild (increase in ALT of 86-171 IU/L above baseline), moderate (increase of 172 to 343 IU/L above baseline), and severe (increase of ≥344 IU/L above baseline). Undetectable serum HBV DNA and hepatitis B e antigen (HBeAg) loss were significantly more likely at the end of follow-up in patients having a flare (P = .0001 and .001, respectively). In the high viremia group, a proportionate increase in virologic response was observed as the degree of flare increased. By multivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predictor for a sustained loss of serum HBV DNA (odds ratio, 5.3; P = .004). Severe flare was predictive of a virologic response in the high but not low viremia group. We conclude that a virologic response in patients with high-level viremia is dependent on the degree of ALT flare. Induction of a robust flare may enhance virologic response when high-level viremia is detected. (HEPATOLOGY 2001;34:1021-1026.)

Occult hepatitis B virus infection: A hidden menace?

SEE ARTICLE ON PAGE 194 Recovery from an acute hepatitis B virus (HBV) infection is associated with loss of HBV DNA from serum, hepatitis B e antigen seroconversion, hepatitis B surface antigen (HBsAg) seroconversion, and normalization of serum aminotransferases. These changes generally imply clearance of virus, but clinical observations have shown that reactivation of HBV infection can occur either spontaneously or after immunosuppression. 1-3 Recent studies showed that immune response to HBV remains vigorous long after an acute infection. In addition, HBV DNA can be detected by polymerase chain reaction (PCR) assays in serum, liver, and peripheral blood mononuclear cells more than a decade after an apparent recovery from HBV infection.4-6 These findings suggest that recovery from acute hepatitis B may not result in complete virus elimination, but rather the immune system keeps the virus at very low levels. There is, however, no clear evidence that patients who have persistently low levels of HBV after recovery from acute hepatitis B develop progressive liver disease. The availability of PCR assays for HBV DNA allows the detection of 10 2 copies/mL compared with 10 6 copies/mL using hybridization assays. Using PCR assays, HBV DNA has been detected in some subjects who are HBsAg negative including those with no serologic markers of HBV infection. In

Hepatitis B virus–specific T-cell proliferation and cytokine secretion in chronic hepatitis B e antibody–positive patients treated with ribavirin and interferon alfa

Immune elimination of hepatitis B virus (HBV) during antiviral therapy depends on the activation of T-cell responses, which are generally impaired in chronic hepatitis B. HBV-specific T helper (Th)-cell reactivity has been assessed post-treatment in liver and peripheral blood of 18 anti-HBe-positive patients with chronic hepatitis B administered combined ribavirin/interferon alfa (IFN-α) therapy. The results showed that patients with undetectable HBV DNA by quantitative polymerase chain reaction under combination therapy were able to mount an HBV-specific CD4 + Th-cell proliferative response and such T-cell reactivity is detectable 1 year after HBV DNA clearance. Hepatitis B virus core (HBcAg) and e (HBeAg) antigen-specific Th-cell proliferation was found more frequently in the liver and peripheral blood in those patients who sustained the alanine aminotransferase (ALT) normalization together with HBV DNA loss. However, HBV-specific IFN-γ production in vitro in peripheral blood mononuclear cells augmented in 4 of 5 sustained responders and all 13 nonresponders, interleukin 10 (IL-10) production decreased in all 5 sustained responders but increased in 7 of 13 nonresponders. Furthermore, intrahepatic HBcAg plus HBeAg-specific Th-cell proliferation only occurred in sustained responders (2 of 3, 67%, vs. 0 of 9; P = .045) whose cells showed in vitro significantly increased productions in HBcAg/HBeAg-specific IFN-γ and IL-12 compared with nonresponders in whom IFN-γ and IL-12 productions decreased together with increased IL-10 secretion. In conclusion this study indicates that combined therapy with ribavirin and IFN-α for chronic hepatitis B not only significantly reduces viremia levels but also induces lasting CD4 + T-cell proliferation and Th1 cytokine release at the site of infection, which may lead to sustained eradication of the HBV.(H EPATOLOGY 2001;33:295-300.)

Acute Exacerbation of Chronic Hepatitis B Virus Infection After Withdrawal of Lamivudine Therapy

Acute exacerbations of chronic hepatitis B virus (HBV) infection occur after withdrawal of lamivudine therapy in approximately 16% of patients and are considered of little clinical significance. We observed “lamivudine withdrawal hepatitis” accompanied by jaundice and incipient liver failure, but also followed by complete recovery and viral clearance. To investigate the incidence, severity, timing, and virologic characteristics of “lamivudine withdrawal hepatitis” we monitored 41 patients for at least 6 months after discontinuation of nucleoside analogue therapy. The incidence of hepatitis flares was estimated to be 7 of 41 (17%); in 2 of 41 cases (5%), hepatitis flares were associated with jaundice and incipient liver failure. A noticeable feature of the “lamivudine withdrawal hepatitis” flares were the high HBV-DNA levels at the time of the alanine transaminase (ALT) peak. All were wild-type HBV, even the one that emerged from a lamivudine-resistant strain during therapy. To minimize the risk of liver failure and to enhance the elimination of HBV following flares, lamivudine therapy was reinstituted in an icteric patient. Clinical and biochemical remission ensued, followed by loss of HBV DNA and hepatitis B e antigen (HBeAg) seroconversion. Such a virologic response did not occur in 5 other patients with a nonicteric “lamivudine withdrawal hepatitis,” who were not retreated with lamivudine. Hepatitis after withdrawal of lamivudine resembles acute hepatitis B with a predominance of anicteric flares within a time frame of 6 months. Active management of hepatitis flares following withdrawal of nucleoside analogue therapy should be investigated further.(Hepatology 2000;32:635-639.)

Loss of serum HBsAg after interferon-A therapy in liver transplant patients with recurrent hepatitis-B infection

Reinfection with hepatitis B virus after orthotopic liver transplantation is nearly universal in patients who have not received posttransplant immunoprophylaxis. Recurrence almost invariably leads to chronic liver disease. Interferon has been used both prophylactically and therapeutically but has not been effective. We treated 2 liver transplant patients with recurrent hepatitis B virus (HBV) infection (serum hepatitis B surface antigen [HBsAg] and HBV DNA positive on polymerase chain reaction, and positive liver biopsy result) with interferon, 3 to 6 MU three times weekly for 6 to 22 months. A full response to therapy was manifested in both patients by normalized serum alanine aminotransferase levels and the loss of serum HBsAg and HBV DNA. The effectiveness of interferon in our patients may have been related to coinfection with hepatitis D virus in the first case and the high interferon dose (6 MU, three times weekly) and long treatment period (22 months) in the second. No episodes of rejection were noted during therapy. We conclude that interferon can induce a complete response in liver transplant patients with recurrent HBV infection. Future studies should investigate the use of interferon therapy at higher doses and/or for longer periods. (Liver Transpl Surg 1997 Jul;3(4):394-7)

Interferon alfa for recurrent hepatitis B infection after liver transplantation.

Reinfection with hepatitis B virus (HBV) after liver transplantation is nearly universal in patients not receiving immunoprophylaxis. Because reinfection reduces graft and patient survival, treatment of recurrent infection is important. Interferon alfa (IFN-alpha) is an effective therapy for chronic hepatitis B infection in immunocompetent patients, but its efficacy in transplant recipients has not been established. Fourteen liver transplant recipients with recurrent hepatitis B infection (hepatitis B surface antigen [HBsAg] positive in serum; hepatitis on biopsy) were treated with IFN-alpha 2b (Intron A; Schering Inc, Kenilworth, NJ) 3 million units (MU) three times weekly for 23.5 weeks (median, range 4 to 41). The primary endpoint was loss of HBV DNA by the b-DNA assay (a virological response). Before treatment, all patients were HBV DNA positive and 9 were hepatitis B e antigen (HBeAg) positive. Pretreatment HBV DNA levels were 6,760 MEq/mL (median, range 2.0 to 11,888 MEq/mL). HBV DNA levels decreased significantly with treatment (P = .03). Four patients had a complete and sustained virological response. Virological responses did not consistently correlate with biochemical response because of concomitant hepatitis C. Two patients had a serological response; 1 lost HBeAg, another lost HBeAg and HBsAg. All responders remained HBV DNA negative in follow-up (mean, 32 months; range, 23 to 40), but 1 patient required retransplantation for cirrhosis. Of the nonresponders, 1 patient required retransplantation for chronic rejection, 3 required retransplantation for recurrent hepatitis B, 3 died with recurrent hepatitis B, and 3 are alive and remain HBV DNA positive. IFN-alpha can induce a sustained serological (14%) and virological response (29%) in liver transplant recipients with recurrent HBV infection.

Interferon alfa treatment of chronic hepatitis B: Randomized trial in a predominantly homosexual male population

Background/Aims : It has been suggested that human immunodeficiency virus (HIV) coinfection and male homosexuality predict poor response to interferon alfa therapy of chronic hepatitis B. The aim of this study was to examine the effect of HIV coinfection on the response of chronic hepatitis B virus (HBV) infection to interferon alfa therapy in a predominantly homosexual male population. Methods : Fifty patients (82% male homosexuals, 50% HIV positive) with evidence of chronic HBV infection were randomized, stratified by HIV status, to undergo either treatment with interferon alfa (10 MU/m 2 three times weekly for 12 weeks) or no treatment. Response was predefined as loss of serum HBV DNA, loss of hepatitis B e antigen, and the appearance of antibody to hepatitis B e antigen. HIV status and the interferon alfa-associated enzyme, 2′,5′-oligoadenylate synthetase, were evaluated as potential predictors of response to therapy. Results : Six treated patients responded with development of antibodies to hepatitis B e antigen ( P < 0.05). HIV-positive patients were about one-fifth as likely to respond to interferon alfa therapy (relative risk, 0.22; 95% confidence interval, 0.03-1.78). Pretreatment alanine aminotransferase levels were significantly higher in responders than in nonresponders ( P = 0.0005). Pretreatment 2′,5′-oligoadenylate synthetase levels did not predict response. Conclusions : Interferon alfa, 10 MU/m 2 three times weekly for 12 weeks, is effective in eradicating HBV replication in a predominantly homosexual male population not coinfected with HIV.