HBsAg Clearance Research Articles

Longer Duration of HBV-Active Antiretroviral Therapy is Linked to Favorable Virological Outcome in HIV-HBV Co-infected Patients

Background: HBV-HIV co-infection is associated with increased liver-related morbidity and mortality. Herein we analyzed HBV-related virologic and clinical outcomes in HBV-HIV patients in the HAART era. Methods: HBsAg positive HIV-infected patients followed at a US academic center between 1990 and 2008 were assessed in a retrospective and longitudinal study. Factors associated with HBsAg and/or HBeAg clearance and with advanced liver disease were evaluated using logistic regression. Results: 72 patients were evaluated. Their median time of follow-up and of adherence to HBV-active HAART were 3 and 1 years, respectively. HBeAg and HBsAg cleared in 17.6% and 5.5% of patients, respectively. More prolonged use of HBV-active HAART predicted clearance of HBeAg (odds ratio [OR] 2.66, 95% CI 1.15–6.16, p = .02) and of HBsAg (OR 1.54, 95% CI 1.02–2.31, p = .04). Patients clearing HBsAg tended to have higher baseline CD4 (mean CD4 counts: 550 vs. 246 cells/mm3; p = .06). Rate of diagnosis of liver-related complications and death were 24.6/1,000 and 10.5/1,000 patient-years, respectively. Higher ALT levels before HAART initiation were associated with the diagnosis of cirrhosis during follow-up (OR 1.02, 95% CI 1.002–1.03, p = .02). Conclusions: Prolonged use of HBV-active HAART favors HBsAg and HBeAg clearance in HIV-HBV co-infected patients. Those with higher ALT levels at presentation have higher risk of being diagnosed with cirrhosis during the first few years of follow-up.

Sustained Response of Hepatitis B e Antigen-Negative Patients 3 Years After Treatment with Peginterferon Alfa-2a

Patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treated with peginterferon alpha-2a with or without lamivudine achieve significantly higher 6-month posttreatment rates of response compared with those treated with lamivudine alone. The durability of <or=3-year posttreatment response was investigated in this study. Patients received peginterferon alpha-2a only (180 microg once weekly; n = 177), in combination with lamivudine (100 mg daily; n = 179) or lamivudine alone (n = 181) for 48 weeks. A total of 315 patients (116, 114, and 85, respectively) participated in this posttreatment observational study. Three years after treatment, the percentage of patients with normal alanine aminotransferase (ATL) was higher for patients treated with peginterferon alpha-2a (31%) than with lamivudine (18%; P = 0.032). Similarly, 28% of patients treated with peginterferon had hepatitis B virus (HBV) DNA levels <or= 10,000 copies/mL versus 15% of patients treated with lamivudine (P = .039). Peginterferon alpha-2a treatment and high baseline ALT level were independent baseline predictors of long-term virologic response (P = .040 and P = .01, respectively). Of the patients who had been treated with a peginterferon alpha-2a-containing regimen, 8.7% cleared hepatitis B surface antigen (HBsAg; 44% of those with undetectable HBV at 3-year posttreatment follow-up) compared with none treated with lamivudine alone. Biochemical and virologic responses were sustained for <or=3 years in approximately 25% of patients given a 48-week course of peginterferon alpha-2a, with or without lamivudine. The increased rate of HBsAg clearance in patients with HBeAg-negative chronic hepatitis B supports the use of peginterferon alpha-2a as a first-line treatment.

Clinical significance of 4 patients with chronic hepatitis B achieving HBsAg clearance by treated with pegylated interferon alpha-2a for less than 1 year: a short report

We report 4 chinese patients with hepatitis B e antigen-positive chronic hepatitis B achieving clearance of HBsAg by using pegylated interferon alpha-2a for less than 1 year, to provide one clinical clue for the treatment of chronic hepatitis B.

Management and prevention of drug resistance in chronic hepatitis B

The management of hepatitis B virus resistance to antivirals has evolved rapidly in recent years. The definition of resistance is now well established, with the importance of partial response and the improvement of assays to detect genotypic resistance and virological breakthrough. Data on phenotypic resistance have allowed to define the cross-resistance profile for the main resistant mutants, providing a rationale for treatment adaptation. Clinical studies have shown that an early treatment intervention in case of a virological breakthrough or a partial response with the addition of a second drug having a complementary cross-resistance profile allows one to maintain the majority of patients in clinical remission. The prevention of resistance should rely on the use of the most potent antivirals with a high genetic barrier to resistance as a first-line therapy. The future perspectives are to design strategies to hasten the HBsAg clearance, which should become a new treatment endpoint, to prevent drug resistance and to decrease the incidence of complications of chronic hepatitis B.

Interferón en la hepatitis B

Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.

Ante-natal screening and post-natal follow-up of hepatitis B in the West Midlands of England

We established at Queen Elizabeth Hospital in Birmingham a post-natal follow-up care service for hepatitis B virus (HBV) positive women diagnosed through ante-natal screening. Virological and clinical follow-up of HBsAg positive mothers detected through ante-natal screening in Birmingham. Retrospective observational study. We evaluated 117 post-natal mothers with chronic HBV infection between April 2003 and December 2006. Patients were first seen at least 3 months post-delivery and followed up. Most of the women were of Asian or African origin (107 of 117 patients). Five out of 117 (4%) patients had undergone serum HBsAg clearance by the time of post-natal review, and 112 patients had persisting HBsAg-positivity (seven HBeAg positive and 105 HBeAg negative). HBeAg positive women were younger than HBeAg negative patients (median 21 vs 30-years old). Fifty percent of HBeAg negative women had detectable serum HBV DNA at the time of initial review. HBeAg positive women had higher serum HBV DNA titres than those negative for HBeAg (median 40 million copies/ml vs 4323 copies/ml). The majority of patients had normal serum transaminases. A single case of clinically significant liver disease was identified in a woman with HBV and delta virus infection. Very few women who were diagnosed with chronic HBV infection at ante-natal screening have clinical evidence of liver disease. However, many have high levels of virus replication and remain at risk for the future development of liver disease.

Lamivudine treatment for severe acute HBV hepatitis

Treatment for acute hepatitis B is recommended in order to reduce the risk of progression to fulminant hepatitis and the need of OLT. We report our experience on treatment with high dose lamivudine, in patients with severe acute HBV infection. The diagnosis was based on clinical and virological findings and exclusion of other known causes of liver damage. The decision to treat was based on the prolongation of INR together with increasing values of bilirubin and ALT. Four patients received Lamivudine 200 mg/daily until clearance of serum HBV-DNA and then 100 mg/daily until clearance of HBsAg and appearance of anti-HBs antibodies. One patient received 100 mg/daily because of chronic renal impairment. The median period of hospitalization was 13 days, and none of the patients had complications, related either to underlying disease or to therapy. The complete normalization of serum transaminases and bilirubin occurred on average after 5.5 weeks and 3 weeks respectively. All patients cleared serum HBV-DNA within three months, lost HBeAg and HBsAg and seroconverted to anti-HBe; four patients developed anti-HBs at a protective titre. Early antiviral treatment attenuates the clinical and biochemical impairment leading to fast healing and promoting complete recovery.

Virological and clinical aspects of HBV‐HCV coinfection in HIV positive patients

In a long-term follow-up study the clinical and virological presentation of HBV/HCV coinfection in anti-HIV positive patients was evaluated. Plasma HBV-DNA, HCV-RNA, and HIV-RNA were determined by PCR in 5 HBsAg/anti-HCV/anti-HIV positive patients, in 4 HBsAg/anti-HIV positive patients and in 82 anti-HCV/anti-HIV positive patients first observed at a Unit of Infectious Diseases in Naples (Italy) from 1990 to 2000 (follow up 6-16 years). All five hepatitis B and C coinfected patients showed reciprocal inhibition of viral replication on admission and during the follow up. At the end of the follow up a clearance of HBsAg from serum was observed in four patients and a clearance of anti-HCV in one of them. In two patients after clearance of HBsAg, evidence of occult HBV infection was observed, at times associated with a hepatic flare. None of the four patients with HIV/HBV coinfection lost HBsAg and none of the 82 with HIV/HCV coinfection lost anti-HCV during the follow up. In anti-HIV positive patients HBV/HCV coinfection is characterized by reciprocal inhibition of viral replication, more evident in HBV expression in plasma and at times by progression to occult HBV infection.

Spectrum of Hepatitis B Infection in Children: Report of 167 Cases from a Developing Country

Purpose: Information regarding the various manifestations of hepatitis B infection in children form developing countries is scanty. We have studied the clinical, biochemical and serological aspects of hepatitis B infection in children. Methods: From January 1998 to May 2007, 167 children (up to 14 years of age) presented with hepatitis B infection to our tertiary care hospital, were studied. Their clinical, biochemical and serological details were recorded in a proforma. Depending upon the serological pattern, the children were classified into acute hepatitis B or AHB (HBsAg & IgM anti HBc positive), chronic hepatitis B or CHB (HBsAg positivity for more than 6 months). The latter group was further subdivided into three; inactive HBsAg carrier (HBsAg, anti HBe positivity & HBeAg negative with ALT< 2 times upper limit of normal [ULN]), replicating virus with activity (HBsAg and HBeAg positive and anti HBe negative with ALT > 2 times ULN), and replicating virus without activity or immune tolerance phase (HBsAg, HBeAg positive and anti HBe negative with ALT <2 times ULN). Results: The mean age was 8.5 ± 3.8 years and 146 of them were male. The proportion of AHB and CHB was 37% & 67% respectively. The source of infection in the majority of AHB was intramuscular injection (53%) & 95% became HBsAg negative after 6 months. Of the 105 CHB children, 76% were incidentally detected and 24% were symptomatic (2% HCC and 22% CLD). Of the 80 incidentally detected children, 37.5% had inactive hepatitis B, 37.5% had replicating HBV without activity and just 25% had replicating HBV with activity. The majority of mothers (61%) of children with immune tolerance phase infection were positive for HBsAg. We managed to give interferon therapy in 20 children and 10 of them (50%) had responded (e-antigen seroconversion). Overall, 9 children died (7 of 10 FHF, and two CLD). Conclusion: In developing countries, almost one third of HBV infections are acute and intramuscular injection is a common source. Like in adults, 95% children too clear HBsAg after an attack of AHB. The majority of CHB in children are incidentally detected and a major portion is perinatally acquired and in immune tolerance phase.

The Role of Viral‐specific Immune Responses on the Outcome of Chronic Hepatitis B (HBV) Infection in Children: New Insights Into Immunopathology

The Role of Viral‐specific Immune Responses on the Outcome of Chronic Hepatitis B (HBV) Infection in Children: New Insights Into Immunopathology

Hepatitis B virus DNA in serum of ‘anti-HBc only’-positive healthy Lebanese blood donors: significance and possible implications

Transmission of HBV infection through transfusion of HBsAg-negative blood has been documented. It is evident that low levels of HBV-DNA remain detectable in serum and liver tissue of some patients who clear HbsAg, and that the detection rate is highest in individuals who are 'anti-HBc positive alone'. This study was designed to assess the frequency and clinical significance of 'anti-HBc alone' in Lebanese blood donors. A total of 5511 blood donor samples from three major hospitals representing most regions of the country were tested for anti-HBc, amongst other screening tests. Samples positive for 'anti-HBc alone' were then tested for HBV-DNA and any positive for HBV-DNA were then genotyped and investigated for hepatitis B viral load. The study showed that 203 (3.7%) of randomly selected Lebanese blood donors were confirmed as 'anti-HBc alone'. Of these, 11 (5.4%) were HBV-DNA positive as detected by nested PCR. All samples had HBV-DNA levels below 400 copies/ml and all were genotype D. It can be concluded that HBV was present, although the circulating amount of virus was below the detectable limit for the assay used. Therefore, routine screening for anti-HBc may be required in Lebanese blood donation centres as an additional preventive measure for controlling transmission of HBV via blood transfusion.

Pegylated interferon-alfa–2a plus adefovir combination therapy is superior to pegylated interferon-alfa–2a alone or adefovir monotherapy in reducing HBsAg levels in HDV-coinfected patients with low HBV viremia

Introduction: Serum HBsAg levels are considered as a surrogate marker for intrahepatic HBV-cccDNA levels and have been shown to be reduced by adefovir therapy in HBV-monoinfected patients. The hepatitis D virus uses the HBsAg for virion formation. Thus, the best treatment option for HDV infection would be clearance of HBsAg.

Antiviral therapy and resistance with hepatitis B virus infection

Hepatitis B virus (HBV) infection is still the most common cause of hepatocellular carcinoma and liver cirrhosis world wide. Recently, however, there has been quite dramatic improvement in the understanding of HBV associated liver disease and its treatment. It has become clear that high viral replication is a major risk factor for the development of both cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine lowers the risk of HBV associated complications. There are currently three nucleos(t)ides licensed, in addition to interferon, and there are more drugs coming to the market soon. Interferon or its pegylated counterpart are still the only options for treatment with defined end points, while nucleos(t)ides therapy is used mostly for long term treatment. Combination therapies have not been shown to be superior to monotherapy in naive patients, however, the outcome depends on how the end point is defined. Interferon plus lamivudine achieves a higher viral suppression than either treatment alone, even though Hbe-seroconversion was not different after a one year treatment. HBV-genotypes emerge as relevant factors, with genotypes "A" and "B" responding relatively well to interferon, achieving up to 20% HBsAg clearance in the case of genotype "A". In addition to having a defined treatment duration, interferon has the advantage of lacking resistance selection, which is a major drawback for lamivudine and the other nucleos(t)ides. The emergence of resistance against adefovir and entecavir is somewhat slower in naive compared to lamivudine resistant patients. Adefovir has a low resistance profile with 3%, 9%, 18%, and 28% after 2, 3, 4, and 5 years, respectively, while entecavir has rarely produced resistance in naive patients for up to 3 years.

Hepatitis B Virus: Something Old, Something New

Hepatitis B Virus: Something Old, Something New

Long‐term surveillance of haematopoietic stem cell recipients with resolved hepatitis B: high risk of viral reactivation even in a recipient with a vaccinated donor

Reactivation of resolved hepatitis B virus (HBV) infection is increasingly recognized in patients with severe immunosuppression. We monitored seven patients with pretransplant antibodies to hepatitis B surface antigen (anti-HBs) and hepatitis B core antigen (anti-HBc) for HBV reactivation after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Reverse seroconversion (from anti-HBs to HBsAg) was observed in six recipients occurring 12, 14, 16, 22, 31 and 39 months after allo-HSCT, respectively. The only patient without HBV reactivation had the highest pretransplant anti-HBs titre and died after the shortest follow-up period (25 months). A novel HBV surface mutant (D144G/G145E) was isolated from one recipient of stem cells from a donor vaccinated against HBV. Another surface mutant (P142L/G145R) was detected in a recipient from a non-immune donor. Serum ALT elevation was measured in only two of the six patients with viral reactivation, followed by spontaneous clearance of HBsAg in one of them. Antiviral treatment reduced viral load in five patients, but the emergence of YMDD motif polymerase mutations resulted in lamivudine resistance in two patients. In conclusion, the risk of reactivation of a resolved HBV infection is close to 100% in allogeneic stem cell recipients and vaccination of the donor does not always warrant reliable protection.

Virological Outcome of Chronic Hepatitis B Virus Infection in HIV-Coinfected Patients Receiving Anti-HBV Active Antiretroviral Therapy

The immune suppression caused by HIV infection accelerates the course of liver disease caused by chronic hepatitis B virus (HBV) infection. We assessed the outcome of HIV/HBV-coinfected patients exposed to highly active antiretroviral therapy (HAART) including anti-HBV active drugs. Baseline and follow-up plasma HBVDNA and HIV-RNA levels, HBV serological markers, and CD4 counts were longitudinally evaluated in all HBsAg(+) individuals with HIV infection on regular follow-up at an urban HIV reference clinic. Out of 79 HBsAg(+) chronic carriers identified, 39 (50%) were HBeAg(+). Lamivudine (3TC) alone had been received by 37% of patients, while 3TC plus tenofovir (concomitantly or consecutively) had been taken by 58% of them. The median follow-up was of 52 months. Loss of HBeAg or HBsAg occurred in 28% (10/36) and 13% (10/75) of patients, respectively. In multivariate analysis, only undetectable plasma HIV-RNA levels [OR 4.58 (95% CI 1.25-16.78); p = 0.02] and greater CD4 gains on HAART [OR 1.003 (95% CI 1.000-1.006); p = 0.03] were associated with undetectable serum HBV-DNA at the end of follow-up. Anti-HBV active HAART makes it possible to achieve HBsAg clearance, anti-HBe seroconversion, and suppression of HBV replication in a substantial proportion of HBV/HIV-coinfected patients, particularly in those with complete HIV suppression and greater immune recovery. Thus, HBV/HIV-coinfected patients might benefit from an earlier introduction of HAART.

Differentiating Acute Hepatitis B from the First Episode of Symptomatic Exacerbation of Chronic Hepatitis B

In countries with intermediate or high endemicity for chronic hepatitis B virus (HBV) infection, exacerbations of chronic hepatitis B (CHB) are common. We studied the clinical, biochemical, and virologic characteristics of patients first presenting clinically with features of acute icteric hepatitis B, to identify features that might differentiate between acute viral hepatitis B (AVHB) from first episode of exacerbation of chronic hepatitis (ECHB). We retrospectively analyzed 79 patients (mean age 35.4 +/- 14 years; M:F = 60:19) who first presented clinically as AVHB, within 4 weeks of onset of symptoms. Patients who on follow-up cleared HBsAg and/or did not develop any clinical, radiologic, or histologic evidence of chronic liver disease (CLD) were categorized as AVHB (group 1). Patients who had persistence of HBsAg and developed clinical, biochemical, radiologic, or histologic evidence of chronic liver disease were categorized as ECHB (group 2). Forty-nine patients were in group 1 and 30 in group 2. The 2 groups were comparable with respect to prodrome, onset of jaundice, serum bilirubin, ALT, prothrombin time prolongation, serum albumin, and A/G ratio. Among group 1 patients, 78% had IgM anti-HBc positive in titers > 1:1000; in group 2, there were negative or positive in titers < 1:1000 in 70% patients (P < .001). Forty-seven of 49 (95.9%) patients in group 1 had HBV-DNA levels < 0.5 pg/mL, whereas 26 of 30 (86.73%) patients in group 2 had levels > 0.5 pg/mL (P < or = .001). Quantitative HBV DNA and IgM anti-HBc titers at initial presentation can differentiate patients with a true episode of acute hepatitis B from patients with first episode of symptomatic exacerbation of chronic hepatitis B. Clinical and biochemical features do not help in differentiating the two.

Treatment options in HBV

The available evidence on interferon-alpha (IFN) treatment for chronic hepatitis B is sufficient to conclude that in patients with HBeAg positive chronic hepatitis, standard IFN therapy significantly improves clearance of HBeAg (number needed to treat [NNT] = 4), loss of HBV-DNA (NNT = 4) and clearance of HBsAg (NNT = 18). HBeAg positive patients with normal or slightly raised ALT should be treated only if there is histological evidence of progressive disease. In patients with HBeAg negative chronic hepatitis, less than 20% of subjects who have achieved an end-of-treatment virological response after a course of standard IFN maintain a sustained virological response in the long-term. IFN treatment could help to delay or prevent disease decompensation and liver-related deaths but further large studies are needed. Lamivudine is effective at reducing, and sometimes clearing, HBV replication in heavily immunosuppressed patients and can be safely administered to patients with advanced liver disease. Lamivudine should be continued over an undefined extended period of time, with a switch from lamivudine to adefovir if there is an HBV-DNA breakthrough under therapy. Adefovir, excluding cost, is preferable to lamivudine as a first-choice because there is less chance of inducing resistance. The long-term benefit of lamivudine and adefovir and the role of combinations is under investigation.

Assessment of treatment efficacy in HBV infection and disease

In patients co-infected with HIV and HBV viral load monitoring allows comparison of the efficacy of different antiviral drugs and determination of the initial response to therapy. Usually, the decline in viral load is associated with an improvement in ALT levels and liver histology scores, but some patients show transient elevations in ALT levels due to the restoration of the specific anti-HBV immune response. Analysis of liver histology is useful to determine the improvement of the inflammatory activity of the disease and liver fibrosis, and to make an accurate diagnosis when drug hepatotoxicity is suspected. HBe seroconversion and HBs loss have been described in some patients during anti-HBV therapy with lamivudine, adefovir or tenofovir, indicating that the control of viral replication by these agents may lead to a dramatic suppression of viral load. HBV drug resistant mutants can be diagnosed at an early stage with the monitoring of viral load. Future research directions include the determination of predictive factors of response, the effect of anti-HBV therapy on liver disease severity, the impact of long-term treatment on HBsAg clearance and intrahepatic cccDNA, the impact of HBV drug resistance on the liver disease, the role of cross-resistance testing of HBV strains in patients with HBV treatment failure.

Clinical and Virological Effects During Two Years of Ongoing Adefovir Dipivoxil in the Treatment of Lamivudine-Resistant Chronic Hepatitis B Infection

Objective Our aim was to evaluate the efficacy and safety of adding adefovir to lamivudine therapy for hepatitis B virus (HBV)-infected patients resistant to Ramivudine. Patients and methods Among 17 studied patients, 7 had chronic active HBV infection and 10 were posttransplant with HBV infection (9 with de novo HBV). They received lamivudine plus adefovir therapy for 2 years. We assessed reductions in serum HBV-DNA and alanine aminotransferase (ALT) levels, loss of HBeAg (in HBeAg+ cases), and HBsAg clearance. Results A virological response, as defined by HBV-DNA below the cut off by hybridization, was observed in 12 (70.6%) patients and loss of HBeAg in 4 (44.4%) of the 9 initially HBeAg-positive cases. A biochemical response, defined as a decreased serum ALT to the normal range, occurred in 4 (26.7%) patients. Median serum creatinine increased in 3 of 15 (20%) patients, excluding those on hemodialysis. There were two noteworthy cases of sustained HBsAg seroconversion with adefovir (11.8%): one patient with de novo HBV infection posttransplantation and positive hepatitis C virus–RNA serology, and one patient with decompensated HBV cirrhosis in whom viral replication ceased, making him eligible for transplantation. Conclusions Currently, adefovir is an effective rescue therapy that broadens the existing range of options for patients with lamivudine-resistant chronic hepatitis B infection, particularly those with decompensated cirrhosis awaiting a liver graft, and those with recurrent posttransplantation HBV. The relatively small biochemical response seen in these patients may be attributable to the high prevalence of concomitant hepatitis C virus infection (41%).