Bulent Degertekin

Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations

BACKGROUND/AIMS We sought to identify mutations associated with treatment failure to adefovir (ADV) and to determine virologic response to tenofovir (TDF) alone and in combination with emtricitabine (FTC) in these patients. METHODS Serum samples prior to and after the change in treatment to TDF/TDF+FTC from 13 patients were analyzed by direct sequencing and clonal analysis. RESULTS ADV-resistant mutations, rtA181V and rtN236T, were detected on direct sequencing in 3 of 8 patients who had virologic breakthrough. Among patients with suboptimal virologic response, rtA181T, rtI233V, and rtN236T were present on clonal analysis in 3 patients. Ten patients received TDF, 8 achieved virologic response. One had ADV-resistance at baseline and persistence of ADV-resistant mutations during TDF treatment, addition of FTC resulted in a further decrease in HBV DNA. Another patient had no ADV-resistance at baseline, and selection of ADV-resistant mutations during TDF treatment. All 3 patients who received TDF+FTC had undetectable HBV DNA within 3-12 months including 2 who had ADV-resistance at baseline. CONCLUSIONS TDF monotherapy is effective for patients with virologic breakthrough or suboptimal response to ADV, but combination therapy with a nucleoside analogue should be considered in patients with ADV-resistance. No novel mutations were detected.

Impact of Virologic Breakthrough and HBIG Regimen on Hepatitis B Recurrence After Liver Transplantation

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre‐OLT and HBIG regimens post‐OLT. Data from the NIH HBV‐OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1–81) post‐OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log10 copies/mL, 74% were receiving antiviral therapy. Twenty‐five patients experienced virologic breakthrough before OLT. Post‐OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high‐dose, IV low‐dose, intramuscular low‐dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre‐OLT as long as rescue therapy is administered pre‐ and post‐OLT.

Update on viral hepatitis: 2008.

Purpose of review The present review is a concise review of recent developments in the field of viral hepatitis, based on publications between December 2007 and November 2008. Recent findings The incidence of acute hepatitis A and B infection has declined significantly, especially among children less than 15 years of age. Five oral antiviral agents have been approved for the treatment of chronic hepatitis B. Telbivudine is more potent than lamivudine but is associated with a high rate of antiviral resistance compared with entecavir or tenofovir. De-novo combination of lamivudine and adefovir reduces the rate of antiviral resistance compared with lamivudine monotherapy. Individualizing dose and duration of pegylated interferon and ribavirin according to on-treatment virologic response may improve sustained virologic response rates. Several specifically targeted antiviral therapies notably protease and polymerase inhibitors are promising but must be used in combination with pegylated interferon and ribavirin. Hepatitis E virus has been reported to result in chronic hepatitis in transplant patients. Summary Multiple treatment options are available for hepatitis B but long-term treatment is required. Several specifically targeted antiviral therapies have shown promise. In the meantime, individualizing dose and duration of pegylated interferon and ribavirin might improve sustained virologic response rates in patients with hepatitis C.

Indications for Therapy in Hepatitis B

Increased treatment options that are more efficacious and safe and new knowledge on the natural history of chronic hepatitis B virus (HBV) infection have expanded the indications for therapy in hepatitis B. The question is no longer “Who should be treated?” but “When should treatment be initiated?” Treatment is clearly indicated in patients with life‐threatening liver disease (acute liver failure, decompensated cirrhosis, or severe hepatitis flare) and in those with compensated cirrhosis and high levels of serum HBV DNA. For patients with precirrhotic liver disease, treatment indications should be based on clinical, biochemical, or histological evidence of liver disease, such as elevated alanine aminotransferase (ALT) levels, abnormal histology, and high levels of serum HBV DNA. The cutoff for ALT and HBV DNA values are constantly being revised and should be set at a lower level for older patients who may have been infected for a longer period of time. High serum HBV DNA levels persisting for a few decades are associated with increased risk of clinical outcomes, but there is insufficient data to support the initiation of treatment based on high serum HBV DNA alone, particularly in young patients, those with persistently normal ALT levels, and those with a single high HBV DNA level. The decision to initiate treatment at the time of assessment or to defer treatment should take into consideration other factors such as desire to start a family, occupational requirement, family history of hepatocellular carcinoma, access to care and insurance coverage, and commitment to long‐term treatment and medication compliance. All patients who are not initiated on treatment should continue to be monitored so treatment can be started if and when the indication arises. (HEPATOLOGY 2009;49:S129–S137.)

Sensitivity and accuracy of an updated line probe assay (HBV DR v.3) in detecting mutations associated with hepatitis B antiviral resistance.

BACKGROUND/AIMS Early detection of antiviral drug-resistant mutations enables prompt initiation of rescue therapy. The aim of this study was to determine the accuracy and sensitivity of a new line probe assay in the detection of antiviral drug-resistant HBV mutations. METHODS One-hundred samples from 54 patients with virologic breakthrough during entecavir, lamivudine or adefovir treatment and 21 samples from 21 nucleoside-naïve patients were tested by direct sequencing and an updated line probe assay (Innogenetics, HBV DR v.3) which incorporates probes that can detect mutations at 11 positions of the reverse transcriptase region of the HBV polymerase gene. RESULTS Complete concordance between line probe and sequencing results was observed for 90/121 samples (74.3%) and 1291/1331 amino acid positions (96.9%). Testing of follow-up samples and clonal analysis of discordant samples confirmed the presence of mutations where line probe assay but not direct sequencing detected mutations. HBV DR v.3 assay consistently detected mutations present in > or = 5% of the virus population when HBV DNA concentration was > or = 4 log10copies/mL. CONCLUSIONS The updated version of the line probe assay (HBV DR v.3) has high concordance with direct sequencing in detecting antiviral drug-resistant mutations but its sensitivity in detecting mutations at some positions needs to be improved.

Liver Transplantation Outcomes Among Caucasians, Asian Americans, and African Americans with Hepatitis B

Several previous studies found that Asians transplanted for hepatitis B virus (HBV) infection had worse post‐transplant outcomes than Caucasians. Data on post‐transplant outcomes of African Americans and waitlist outcomes of Asian Americans and African Americans with hepatitis B are scant. The aim of this study was to compare waitlist and post‐transplant outcomes among Asian Americans, African Americans, and Caucasians who had HBV‐related liver disease. Data from a retrospective‐prospective study on liver transplantation for HBV infection were analyzed. A total of 274 patients (116 Caucasians, 135 Asians, and 23 African Americans) from 15 centers in the United States were enrolled. African Americans were younger and more Asian Americans had hepatocellular carcinoma (HCC) at the time of liver transplant listing. The probability of undergoing transplantation and the probability of survival on the waitlist were comparable in the 3 racial groups. Of the 170 patients transplanted, 19 died during a median follow‐up of 31 months. The probability of post‐transplant survival at 5 years was 94% for African Americans, 85% for Asian Americans, and 89% for Caucasians (P = 0.93). HCC recurrence was the only predictor of post‐transplant survival, and recurrence rates were similar in the 3 racial groups. Caucasians had a higher rate of HBV recurrence: 4‐year recurrence was 19% versus 7% and 6% for Asian Americans and African Americans, respectively (P = 0.043). In conclusion, we found similar waitlist and post‐transplant outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B. Our finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies. Liver Transpl 15:1010–1020, 2009.

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study.

Han SH, Reddy KR, Keeffe EB, Soldevila‐Pico C, Gish R, Chung RT, Degertekin B, Lok ASF. Clinical outcomes of liver transplantation for HBV‐related hepatocellular carcinoma: data from the NIH HBV‐OLT study. 
Clin Transplant 2011: 25: E152–E162.

When to Start and Stop Hepatitis B Treatment : Can One Set of Criteria Apply to All Patients Regardless of Age at Infection?

Existing guidelines for the treatment of hepatitis B virus (HBV) infection recommend that only patients with active or advanced liver disease and high serum HBV DNA levels be treated and that, in patients who are initially seropositive for hepatitis B e antigen (HBeAg), treatment can be stopped 6 months after HBeAg seroconversion (13). In this issue, Lai and Yuen (4) raise concern that those recommendations are inappropriate for patients with perinatal HBV infection. They propose that patients with normal alanine aminotransferase (ALT) levels who acquire infection early in life should also be treated and that HBeAg-positive patients should continue treatment after HBeAg seroconversion. The 2007 update of the American Association of the Study of Liver Disease guidelines (5) address some of Lai and Yuens concerns by recommending that treatment also be considered for patients with intermittent or mildly elevated ALT levels; those who remain HBeAg- positive with high serum HBV DNA levels after 40 years of age; and HBeAg-negative patients with HBV DNA levels of 10000 to 100000 copies/mL (2000 to 20000 IU/mL), particularly if liver histologic examination shows significant inflammation or fibrosis (5). Here, we put other aspects of their proposal in the context of existing evidence. People with ALT values within the normal range are traditionally considered to have healthy livers. However, recent evidence suggests that the upper limits of normal in most diagnostic laboratories are erroneously high, owing to inclusion of patients with asymptomatic liver disease (6). Two studies reported that persons with ALT levels that are 0.5 to 1 times greater than the upper limit of normal had higher mortality from liver disease or cirrhosis complications than did persons with ALT levels less than 0.5 times the upper limit of normal (7, 8). Small studies have also found that up to one third of HBV carriers with normal ALT levels have moderate inflammation or advanced fibrosis (9, 10). However, the natural course of chronic HBV infection varies and may be punctuated by recurrent fluctuations in serum HBV DNA and ALT levels (11), and a study from Taiwan found that disease progressed slowly among HBeAg-positive patients with normal ALT levels: The cumulative probability of cirrhosis after 17 years was 12.6%, and none of the 240 patients developed hepatocellular carcinoma (12). These latter data suggest that treatment can be deferred in most patients with persistently normal ALT levels and that the presence of risk factors for progressive liver disease, such as older age, HBeAg positivity, high serum HBV DNA levels, and co-infection with hepatitis C or D virus, can be used to identify patients with normal ALT levels who warrant further evaluation and treatment. Hepatitis B e antigen seroconversion was long thought to be associated with cessation of HBV replication and remission of liver disease. However, evidence from the past 2 decades shows that HBV DNA remains detectable in serum after HBeAg seroconversion, albeit at low levels (13). In some patients, high serum HBV DNA levels and active liver disease persist after HBeAg seroconversion (HBeAg-negative chronic hepatitis), a state frequently associated with precore HBV variant (14) and HBV genotype D (and less commonly genotype B and C) infection. The recognition that HBV persists after HBeAg seroconversion has led to the term inactive carrier state, with the understanding that the virus is not eradicated and liver disease can become active again. Nevertheless, a study from Taiwan found that two thirds of patients with perinatal HBV infection had sustained remission and very low risk for cirrhosis and hepatocellular carcinoma up to 9 years after spontaneous HBeAg seroconversion (15). On the basis of these data, HBeAg seroconversion seems an appropriate treatment end point in most patients, provided that they continue to be monitored and treatment is reinitiated when hepatitis is reactivated. This is particularly true when a strict definition of HBeAg seroconversionnamely, HBeAg loss, HBe antibody detection, a nondetectable (or very low) serum HBV DNA level, and normalization of ALT valuesis used as the treatment end point. The major difference between perinatal and adult-acquired HBV infection is the presence of a long immune tolerance phase (10 to 40 years) in patients with perinatal HBV infection, during which patients are HBeAg-positive with a high serum HBV DNA level but a normal ALT level (11). Patients in this phase have a very low rate of spontaneous or treatment-related HBeAg seroconversion. Available data suggest that the next phases of immune clearance (HBeAg positivity, high HBV DNA levels, and high ALT levels) and inactive carrier state (HBeAg negativity, low or undetectable HBV DNA levels, and persistently normal ALT levels) are similar for patients with perinatal or adult-acquired HBV infection. Some patients will progress from the inactive carrier state to HBeAg-negative chronic hepatitis. This transition is not unique to patients with perinatal HBV infection; in fact, it is most commonly associated with HBV genotype D, which is usually acquired during childhood or during adulthood. The basis for existing recommendations to defer treatment in HBeAg-positive patients with normal ALT levels is the low rate of HBeAg seroconversion with treatment and the generally slow rate of disease progression during the immune tolerance phase in patients with perinatal infection. Although HBV replication after HBeAg seroconversion can be reactivated in all patients independent of age at infection, an occurrence of 30% over 10 years (15) does not justify continuing treatment for all patients. Beyond questions about when to start and stop treatment, Lai and Yuens proposal reflects the conviction that the ideal treatment end point, permanent suppression of HBV DNA to undetectable levels on polymerase chain reaction, can be achieved with current therapies. Available data suggest that after a 1-year course of pegylated interferon therapy, sustained HBeAg seroconversion is achieved in only approximately 30% of HBeAg-positive patients and sustained suppression of serum HBV DNA to undetectable levels is achieved in approximately 20% of HBeAg-negative patients (5). A 1-year course of oral nucleoside therapy (lamivudine, adefovir, entecavir, or telbivudine) results in undetectable serum HBV DNA in 20% to 70% of HBeAg-positive patients and 50% to 90% of HBeAg-negative patients (5). However, viral relapse occurs in more than 90% of patients after treatment withdrawal, except in patients who have sustained HBeAg seroconversion or the rare patient who has cleared HBsAg (16). Extending treatment with lamivudine or telbivudine beyond 1 year is associated with a decreasing proportion of patients with undetectable serum HBV DNA because of selection of drug-resistant mutants. Continued treatment for HBeAg-negative patients with adefovir for up to 5 years has been reported to increase the proportion of patients with undetectable serum HBV DNA from 72% at the end of 1 year to 80% at the end of 2 years, with a subsequent decrease to 67% at the end of 5 years (17). Preliminary data indicate that treating HBeAg-positive patients with entecavir for up to 3 years resulted in undetectable serum HBV DNA in 87% of patients (18). These long-term efficacy data are based on few patients: 70 for adefovir and 122 for entecavir. More important, viral suppression will not be permanent in all patients, given that the rate of drug resistance will increase with duration of treatment even with new drugs (such as entecavir) and nonadherence to therapy is more likely over time. Finally, most clinical trials enroll only patients with elevated pretreatment ALT levels; response rates may be lower in patients with normal ALT levels. A high pretreatment ALT level is the best predictor of interferon- and nucleoside treatmentrelated HBeAg seroconversion (19). Thus, although currently approved treatments can suppress serum HBV DNA to undetectable levels on polymerase chain reaction, no data show yet that any of these treatments can result in permanently undetectable virus in all patients. Because HBV cannot be eradicated, many physicians have argued that patients with hepatitis B should receive lifelong treatment, as is given for other chronic medical illnesses. However, rates of drug resistance increase with duration of treatment (even with new therapies), long-term safety data are lacking, and treatment is very expensive (approximately

Impact of the hepatitis B virus genotype on pre– and post–liver transplantation outcomes†

18000 per year for pegylated interferon and

Characteristics of chronic hepatitis B patients who underwent liver biopsies

2500 to