Hepatitis: Perrillo RP

Perrillo RP. · No affiliation provided · Hepatology. · Pubmed #19330864 No free full text.

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Perrillo RP, Eason JD. · No affiliation provided · Liver Transpl. · Pubmed #16035070 links to  free full text

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Perrillo RP. · No affiliation provided · Hepatology. · Pubmed #12395311 No free full text.

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Perrillo RP. · No affiliation provided · Hepatology. · Pubmed #10960466 No free full text.

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Gish RG, Perrillo RP, Jacobson IM. · Division of Hepatology and Complex GI, Physicians Foundation, California Pacific Medical Center, 2340 Clay Street, San Francisco, CA 94115, USA. · Semin Liver Dis. · Pubmed #17701845 No free full text.

Abstract: As of October 2006, 6 medications are approved in the United States for the management of chronic hepatitis B virus (HBV) infection: 2 formulations of interferon and 4 oral nucleos(t)ide analogues. For the treating practitioner, tailoring the pharmaceutical regimen according to patient features and clinical circumstances can be a challenge. First-line therapeutic regimens for the management of HBV infection include monotherapy with a U.S. Food and Drug Administration-approved agent that has potent on-treatment viral response and low rates of resistance; in the future, these regimens may include a combination of more than one nucleos(t)ide analogue or a combination of a nucleos(t)ide analogue and pegylated interferon. The oral nucleos(t)ide analogues are generally better tolerated than interferon; however, they can be expensive when administered for lengthy periods and can also lead to medication resistance. Lamivudine, the first approved nucleoside analogue for the treatment of HBV infection, has a very high resistance profile; in fact, lamivudine exposure increases viral resistance to other commercially available nucleos(t)ide analogues: entecavir, telbivudine, and adefovir. For these reasons, the 2007 American Association for the Study of Liver Diseases (AASLD) guidelines no longer recommend lamivudine as first-line therapy for the management of HBV infection. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented approaches to customizing the management of chronic HBV infection. The presentation highlighted recent findings suggesting that early, profound, and sustained viral suppression improves the probability of sustained virologic response and reduces the likelihood of nucleos(t)ide resistance.

Perrillo RP, Jacobson IM. · Hepatology Division, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA. · Semin Liver Dis. · Pubmed #17701844 No free full text.

Abstract: The 2007 American Association for the Study of Liver Diseases (AASLD) practice guidelines for managing chronic hepatitis B virus (HBV) infection recommend pharmacologic therapy for patients with alanine aminotransferase (ALT) activity higher than 2 times the upper limit of normal and serum HBV DNA concentration higher than 20,000 IU/mL. Findings reported over the past several years, however, indicate that HBV infection associated with ALT activity and serum HBV DNA concentrations below these treatment thresholds can progress to serious liver disease, such as cirrhosis or hepatocellular carcinoma. These findings suggest that these treatment thresholds may be too conservative. Moreover, emerging data suggest that, in some patient populations, the appropriate goal of therapy may be sustained suppression of HBV DNA with maintenance antiviral therapy. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented new findings relative to the course of HBV infection.

Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA. · Hepatology. · Pubmed #16447260 No free full text.

Abstract: The practicing clinician is currently faced with a number of treatment options for chronic hepatitis B. Beginning in 1998 with the licensing of lamivudine and subsequently adefovir, the treatment paradigm shifted from 4 to 6 months of conventional alfa interferon to a year of nucleoside analog therapy. However, prolonged treatment with nucleoside analogs is often needed to optimize virological response. Recently, a 48-week regimen of pegylated interferon for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B has been shown to be effective, and long-term nucleoside analog therapy has been demonstrated to maintain viral suppression. These findings have added to the complexity of decision-making and have raised questions about whether a finite course of pegylated interferon or nucleoside analog therapy, with possible long-term maintenance, is better as first-line therapy. Each of these fundamentally different approaches has advantages and limitations, and both have a place in the therapeutic armamentarium against chronic hepatitis B. Long-term therapy with nucleoside analogs, however, raises a number of practical concerns that have not been fully addressed as of yet. I will present evidence in support of the recommendation that antiviral therapy should ideally be directed toward achieving the highest rate of viral clearance with the shortest interval of treatment.

Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA. · Semin Liver Dis. · Pubmed #16103978 No free full text.

Abstract: Nucleoside analogue therapy allows safe, long-term suppression of hepatitis B virus (HBV) and is a major milestone in the treatment of chronic hepatitis B. Entecavir has recently been approved by the U.S. Food and Drug Administration and is not only more potent than lamivudine and adefovir, but it is also associated with a very low rate of drug resistance. Peginterferon, which has been shown to be more potent than conventional interferon, has recently been licensed in Europe and in the United States. Despite these advances, however, the clinician still faces several challenges in treating this relatively complex disorder. Controversies and unresolved issues remain, including the question of whether the thresholds for alanine aminotransferase and HBV DNA levels recommended in the published treatment guidelines are too restrictive. Another complication is the differing levels of sensitivity and dynamic range of the assays for serum HBV DNA. Finite courses of treatment are associated with low rates of virologic response, but drug resistance occurs when nucleoside analogue monotherapy is used long term. The role for combination therapy remains unclear. Much has been accomplished over the past decade, but much remains to be done.

Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA. · Semin Liver Dis. · Pubmed #15192798 No free full text.

Abstract: The development of nucleoside analogues has been a major advance in the treatment of hepatitis B; however, prolonged monotherapy is associated with drug resistance. Currently, no data in humans indicate that a combination of nucleoside analogues leads to enhanced efficacy. New nucleoside analogues with greater inhibitory effects on hepatitis B virus (HBV) replication being developed could prove to be more effective or less likely to be associated with viral resistance. Interferon still has a role to play in the management of chronic HBV infection. Recent data indicate that the response to interferon may be determined in part by differences in genotype. From a theoretical perspective, a combination of pegylated interferon with one or more nucleosides could induce a higher rate of virological response. Additional studies are needed to further address these issues.

Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, Clinical Professor of Medicine, Tulane University School of Medicine, 1514 Jefferson Highway, New Orleans, LA 70121, USA. · J Hepatol. · Pubmed #14708700 No free full text.

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Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70124, USA. · Curr Gastroenterol Rep. · Pubmed #11825543 No free full text.

Abstract: There are two licensed drugs for chronic hepatitis B virus (HBV), interferon alfa and lamivudine, with similar efficacy rates. Lamivudine is less expensive and better tolerated than interferon alfa and is the drug of choice for patients with decompensated cirrhosis and recurrent HBV infection after liver transplantation. The major problem with lamivudine monotherapy has been the emergence of drug-resistant HBV polymerase (YMDD) mutants. Thus, long-term use of lamivudine in other settings remains somewhat controversial. Alternative nucleoside analogues that are active against both wild-type and YMDD-mutant HBV are currently being tested. It is hoped that a combination of one or more of these agents with lamivudine will not only prove more effective than lamivudine alone but also decrease the rate of lamivudine resistance. Preliminary studies suggest that the combination of interferon and lamivudine is associated with an enhanced rate of virologic response when compared with either agent alone. From a theoretical perspective, the combination of interferon with one or more nucleoside analogues may be the most effective way to treat HBV infection in many clinical situations.

Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana 70121, USA. · Gastroenterology. · Pubmed #11231956 No free full text.

Abstract: Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations. Reactivation is frequently induced by medical treatments such as cancer chemotherapy, antirejection drugs used in organ transplantation, and corticosteroids. The immunologic flares that often result from sudden withdrawal of these medications can be life-threatening unless recognized and treated promptly with antivirals, and there is increasing experience that preemptive antiviral treatment can diminish their occurrence and improve the outcome. The experience with lamivudine and other nucleoside analogues has increased our understanding of the molecular events behind hepatitis flares that occur when chronic hepatitis B is treated with drugs that potently inhibit HBV DNA polymerase. However, not all flares are explainable by events related to HBV infection alone. Depending on the population studied, as many as 20%-30% of flares may be caused by infection with other hepatotropic viruses, and this situation may inhibit HBV replication. Proper understanding of the etiology and effective treatment of acute flares in chronic hepatitis B requires an appreciation of high-risk clinical situations, assessment of HBV replication status, and testing for other viruses when appropriate.

Perrillo RP. · Department of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, LA 70121, USA. · Clin Transplant. · Pubmed #10965961 No free full text.

Abstract: Hepatitis B infection of a liver allograft can have serious consequences including a negative influence on the probability of survival. Therefore, there is a need for very effective antiviral therapy for transplant recipients. In this article the early experience with nucleoside analogue antiviral agents, both to prevent and to treat hepatitis B in liver allografts, is reviewed. There are several important characteristics of these agents that are already apparent. Ganciclovir and famciclovir have limited efficacy in treating infections when they are used alone. These compounds might be beneficial if used after resistance develops to other drugs or when used in combination with other agents. Lamivudine is effective for about two-thirds of patients in preventing and treating hepatitis B infection in allografts. Hepatitis B immune globulin (HBIg) is known to increase the efficacy of lamivudine in preventing infection. A large study to further characterize this combination therapy is being organized. Resistance to famciclovir and lamivudine can occur if they are used alone for a long time. In order to lower the incidence of drug resistance, it may be necessary to utilize combinations of nucleoside analogues.

Perrillo RP, Kruger M, Sievers T, Lake JR. · Ochsner Clinics, New Orleans, Louisiana, USA. · Semin Liver Dis. · Pubmed #10895439 No free full text.

Abstract: Liver transplantation in patients infected with hepatitis B virus (HBV) commonly results in reinfection that, if untreated, often compromises the viability of the allograft and negatively influences survival. Posttransplant treatment with hepatitis B immune globulin (HBIG) is now the standard of care, but patients appear to require lifelong treatment to prevent reinfection. In the past several years, new management strategies in patients with HBV have been developed, with an aim to decrease HBV-DNA replication before transplantation. Such an approach should increase the success of transplantation by decreasing the risk of reinfection and thus preventing recurrent disease posttransplantation. Nucleoside analogues, either alone or in conjunction with HBIG, are currently in use and are being studied in clinical trials as a means of preventing viral recurrence. Ganciclovir, famciclovir, and lamivudine all have demonstrated efficacy, although they vary in terms of effectiveness. Resistance may develop with the use of these agents and leads to reinfection by the mutant virus. Combination therapy may minimize the risk of viral mutation. Research continues to search for more effective ways to prevent and, if necessary, treat viral recurrence in patients undergoing liver transplantation for HBV.

Younossi ZM, Perrillo RP. · Department of Gastroenterology, Cleveland Clinic Foundation, Ohio 44195, USA. · Semin Liver Dis. · Pubmed #10349697 No free full text.

Abstract: Although alpha interferons are currently the standard treatments for chronic hepatitis C, they are effective in only 15% to 20% of patients. This low success rate has prompted research into new approaches for maximizing responses to alpha interferons. A variety of drugs have been investigated alone or in combination with alpha interferons. Of these agents, ribavirin is currently the most promising adjuvant, and the combination therapy of ribavirin plus recombinant interferon alfa-2b is reviewed in detail elsewhere in this issue (see Davis article, pp. 49-55; and McHutchison article, pp. 57-65). This article reviews the literature concerning studies of amantadine, rimantadine, ursodeoxycholic acid (UDCA), and nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most commonly used alternatives to ribavirin. As of this writing, virologic response rates have been unsatisfactory when these agents are used as monotherapies. Furthermore, combining alpha interferons with either UDCA or NSAIDs does not appear to improve sustained virologic response rates. However, combination regimens composed of an alpha interferon plus amantadine, or an alpha interferon plus rimantadine, or triple therapy with either amantadine or rimantadine plus an alpha interferon and ribavirin, warrant further investigation.

Nair S, Diehl AM, Wiseman M, Farr GH, Perrillo RP. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA. · Aliment Pharmacol Ther. · Pubmed #15225167 links to  free full text

Abstract: BACKGROUND: Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease. AIM: A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease. METHODS: In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology. RESULTS: Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis. CONCLUSION: Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.

Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, de Man RA, Goodman Z, Condreay LD, Crowther LM, Woessner MA, McPhillips PJ, Brown NA, Anonymous00314. · Division of Hepatology, University of Miami, Jackson Medical Towers, 1500 N.W. 12th Avenue, Suite 1101, Miami, FL 33136, USA. · J Hepatol. · Pubmed #12763376 No free full text.

Abstract: BACKGROUND/AIMS: Lamivudine is effective in treatment-naive patients with chronic hepatitis B, but its role in interferon nonresponders has not been described. We assessed lamivudine treatment, with or without added interferon, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had failed interferon therapy previously. METHODS: Patients were randomized to lamivudine (100 mg) or placebo for 52 weeks or to a 24-week regimen of lamivudine plus interferon. Primary treatment comparisons were at week 52, with a 16-week posttreatment follow-up period. Measurements included histology (primary endpoint), HBeAg response, normalization of alanine aminotransferase, reduction of hepatitis B virus (HBV) DNA, and safety. RESULTS: Among 238 patients, histologic response was significantly more common in patients treated with lamivudine (52 versus placebo 25%, P=0.002) or the combination regimen (32%, P=0.01). HBeAg loss was also more common with lamivudine (33 versus 13 versus 21%), as were virologic and alanine aminotransferase responses. Among 28 subjects with HBeAg loss/seroconversion, 71% had durable responses 16 weeks posttreatment. CONCLUSIONS: Lamivudine for 52 weeks is as effective in interferon nonresponders as in previously reported treatment-naive patients; however, a combination of lamivudine for 24 weeks and interferon for 16 weeks was not effective in this population.

Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, Heathcote EJ, Brown NA, Atkins M, Woessner M, Gardner SD. · Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA. · Hepatology. · Pubmed #12085364 No free full text.

Abstract: Elevated alanine transaminase (ALT) levels and low serum hepatitis B virus (HBV) DNA predict a higher likelihood of hepatitis B e antigen (HBeAg) loss in patients with chronic hepatitis B treated with interferon. Predictors of HBeAg loss in patients treated with lamivudine are not known. The objective of this analysis of 4 lamivudine-controlled Phase III trials was to determine patient-dependent or laboratory variables that predict HBeAg loss. Predictors of HBeAg loss in patients treated with interferon, lamivudine plus interferon, or placebo are also described. A total of 805 adults with chronic hepatitis B were treated either with lamivudine (n = 406), matching placebo (n = 196), interferon (n = 68), or the combination of lamivudine plus interferon (n = 135). Demographic and baseline disease characteristics were used in stepwise multivariate analyses to identify features that were predictive of lamivudine-induced HBeAg loss. HBeAg loss correlated with increased pretreatment ALT levels in all groups. The rate of HBeAg loss was highest among patients with pretreatment ALT levels greater than 5 times the upper limit of normal (ULN) and was most pronounced in the lamivudine group (56%). Multivariate modeling indicated that elevated baseline ALT levels (P <.001) and histologic activity index (HAI) score (P <.001) were important predictors of HBeAg loss in response to lamivudine. The effect of pretreatment ALT levels on HBeAg loss was similar for Asians and Caucasians. In conclusion, elevated pretreatment ALT levels and/or active histologic disease were the most important predictors of lamivudine-induced HBeAg loss. Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels.

Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, Martin P, Dienstag J, Adams P, Dickson R, Anschuetz G, Bell S, Condreay L, Brown N, Anonymous00318. · Section of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, LA 70121, USA. · Hepatology. · Pubmed #11172345 No free full text.

Abstract: Seventy-seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty-seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7-48.5) in the transplanted patients and 26 months (range, 0.1-37) in the nontransplanted group. Twenty-five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow-up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV-DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV-DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine-treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy.

Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA. · Liver-Biliary-Pancreas Center, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston 02114, USA. · N Engl J Med. · Pubmed #10528035 links to  free full text

Abstract: BACKGROUND AND METHODS: Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS: Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS: In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

Sung JJ, Lai JY, Zeuzem S, Chow WC, Heathcote EJ, Perrillo RP, Brosgart CL, Woessner MA, Scott SA, Gray DF, Gardner SD. · Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, People's Republic of China. · J Hepatol. · Pubmed #18329126 No free full text.

Abstract: BACKGROUND/AIMS: We aimed to evaluate nucleoside/nucleotide combination therapy in treatment-naïve HBeAg-positive patients with chronic hepatitis B (CHB). METHODS: One hundred and fifteen HBeAg-positive patients received lamivudine 100 mg daily plus placebo (monotherapy) or lamivudine 100 mg plus adefovir dipoxil 10 mg daily (combination therapy) for 104 weeks in a randomized double-blind study. RESULTS: Time-weighted average change in serum HBV DNA from baseline up to week 16 was -4.20 log(10)copies/mL for both groups (p=0.936). At week 104, median serum HBV DNA change from baseline (log(10)copies/mL) for monotherapy and combination therapy was -3.41 versus -5.22, respectively. HBV DNA breakthrough was detected in 44% of monotherapy and 19% of combination therapy patients. The M204V/I mutation was detected in 43% (15/35) and 15% (6/41) of each group, respectively. ALT normalization at week 100 and 104 was 34% (19/56) in the monotherapy group and 45% (23/51) in the combination therapy group (p=0.018). By week 104, HBeAg seroconversion occurred in 20% of monotherapy and 13% of combination therapy patients. Both regimens were well tolerated. CONCLUSIONS: Lower rates of resistance to lamivudine, lower serum HBV DNA levels and higher rates of ALT normalization were seen in the combination therapy group after two years. However, serological outcomes were similar.

Anderson RD, Chinnakotla S, Guo L, Perrillo RP, Klintmalm GB, Davis GL. · Department of Medicine, Baylor Uinversity Medical Center and the Baylor Regional Transplant Institute, Dallas, TX, USA. · Clin Transplant. · Pubmed #17645711 No free full text.

Abstract: High titer hepatitis B immunoglobulin (HBIG) has significantly reduced the recurrence of hepatitis B virus (HBV) infection after liver transplantation. We compared our experience with intramuscular (IM) HBIG prophylaxis to our earlier outcomes with intravenous (IV) HBIG and other regimens. Methods: One hundred and twenty-three patients with acute or chronic hepatitis B underwent liver transplant at the Baylor Regional Transplant Center between July 1985 and July of 2005. Of these, 63 (43%) received long-term low-dose IM (n = 17) or high-dose IV (n = 46) HBIG. All patients in IM group also received a nucleoside before and after transplant. These patients were compared with those transplanted earlier who received either no prophylaxis (n = 16) or HBIG on day zero and one only (n = 44). Results: HBV recurrence was significantly lower in patients who received long-term HBIG [9/38 (23.7%) for IV and 1/17 (5.9%) for IM] compared with patients who received no treatment (8/11; 72.7%) or only two doses of HBIG (32/40; 80.0%). Two-yr actuarial survivals were 89%, 88%, 54%, and 64%, respectively. Patients on long-term HBIG by either parenteral route survived as well as patients transplanted for other indications. Post-transplant recurrence of hepatitis B in the long-term HBIG groups was usually controlled by intensifying antiviral therapy. Conclusion: Long-term low-dose IM and high-dose IV HBIG are equally efficacious with similar survival and early hepatitis recurrence rates. Graft loss is usually avoidable when recurrence is discovered early and aggressively treated. The IM route is preferable to IV administration due to its ease of administration and lower cost.

Wong SN, Reddy KR, Keeffe EB, Han SH, Gaglio PJ, Perrillo RP, Tran TT, Pruett TL, Lok AS. · Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0362, USA. · Liver Transpl. · Pubmed #17154401 links to  free full text

Abstract: Patients with hepatocellular carcinoma (HCC) receive a higher MELD score and may undergo liver transplantation (OLT) earlier compared to patients with cirrhosis, potentially decreasing waiting list mortality. However, post-OLT survival may be reduced by recurrence of HCC. We compared clinical outcomes between patients with HBV-cirrhosis and no HCC and patients with HBV-HCC. A total of 279 patients (HBV-cirrhosis = 183; HBV-HCC = 96) in the US HBV-OLT study were followed for a median of 30.2 months from listing. Patients with HCC were older, more likely to be Asian, and had less severe liver impairment than patients with HBV-cirrhosis. Despite a higher rate of OLT in patients with HCC (78.1% vs. 51.4%; P < 0.001), intention-to-treat (ITT) survival (73% vs. 78%) and survival without OLT (82% vs. 79%) at 5 years were similar for patients with and without HCC. Cox regression analysis identified higher albumin, lower MELD, no HCC at listing, and being transplanted to be associated with better ITT survival. Ninety-four patients with HCC (including 19 new HCC) and 75 with HBV-cirrhosis underwent OLT. Post-OLT survival (83% vs. 90%) and HBV recurrence (11% vs. 10%) at 3 years were similar, while disease (HBV and/or HCC) recurrence (19% vs. 10%; P = 0.043) was higher in patients with HBV-HCC vs. HBV-cirrhosis. Disease recurrence was the only independent predictor of post-OLT survival. In conclusion, despite more advanced liver disease and a lower rate of transplantation, ITT survival of patients listed for HBV-cirrhosis was comparable to those with HBV-HCC, possibly related to beneficial effects of antiviral therapy.

Perrillo RP, Gish RG, Peters M, Keeffe EB, Alberti A, Buti M, Cooksley WG, Fried MW, Hadziyannis SJ, Liaw YF, Naoumov NV, Schiff ER, Thio CL, Tsai N, Schalm S. · Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA. · Clin Gastroenterol Hepatol. · Pubmed #16469685 No free full text.

Abstract: BACKGROUND & AIMS: Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. METHODS: A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. RESULTS: With the exception of 2 statements, the experts' responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. CONCLUSIONS: Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree.

Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS, Luketic VA, Terrault N, Lok AS, Anonymous00213. · Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. · Hepatology. · Pubmed #12939588 No free full text.

Abstract: Variants in the precore (G(1896)A) and core promoter (A(1762)T, G(1764)A) regions of hepatitis B virus (HBV) may be related to serum HBV DNA levels and severity of liver disease. The aims of this nationwide study were to determine the prevalence of HBV precore/core promoter variants in the United States and the association between these variants and patient demographics, HBV genotypes, serum HBV DNA level, and severity of liver disease. A total of 694 consecutive chronic HBV-infected patients seen in 17 U.S. liver centers during a 1-year period were enrolled. Demographic, clinical, and laboratory data were collected. Sera were tested for HBV genotypes as well as precore and core promoter variants by line-probe assays. Quantitative HBV DNA levels were determined using Cobas Amplicor HBV Monitor kits. Precore and core promoter variants were found in 27% and 44% of patients with chronic HBV infection in the United States. Precore and core promoter variants were more common in hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients (precore, 38% vs. 9%; core promoter, 51% vs. 36%; respectively, P <.001). The prevalence of these variants was related to ethnicity, place of birth, and HBV genotypes. Patients with core promoter variants were more likely to have hepatic decompensation. Precore and/or core promoter variants were associated with higher serum HBV DNA levels in HBeAg-negative but not in HBeAg-positive patients. In conclusion, HBV precore and core promoter variants are not rare in the United States. Physicians should be aware of the existence of HBV precore and core promoter variants and the clinical condition of "HBeAg-negative chronic hepatitis.";