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Li W, Han M, Li Y, Chen D, Luo X, Ning Q. Antiviral resistance mutations potentiate HBV surface antigen-induced transcription of hfgl2 prothrombinase gene. BIOCHEMISTRY (MOSCOW) 2011; 76:1043-50. [PMID: 22082274 DOI: 10.1134/s0006297911090094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antiviral resistance mutations in the hepatitis B virus (HBV) polymerase (pol) gene have been demonstrated to play an important role in the progression of liver disease and the development of hepatocellular carcinoma. The HBV pol gene overlaps the S gene encoding surface antigen (HBsAg). Previous studies from our laboratory have shown that HBV core protein (HBc) and X protein (HBx), but not HBV S protein (HBs), promote hfgl2 prothrombinase transcription. To investigate whether the nucleotide (nucleoside)-induced resistant mutations of HBs potentiate transcription of hfgl2 prothrombinase gene, we generated two mutant HB expression constructs harboring rtM204V/sI195M or rtM204I/sW196L mutations. Two mutant expression plasmids were co-transfected with hfgl2 promoter luciferase-reporter plasmids and β-galactosidase plasmid in CHO cells and HepG2 cells, respectively. Luciferase assay showed that the rtM204I/V mutant HBs could activate the transcription of hfgl2 promoter compared with the wild type HBs. Site-directed mutagenesis and further experiment (co-transfection) demonstrated that transcription factor Ets translocated to its cognate cis-element in the hfgl2 promoter. The results show that mutated HBs caused by antiviral drug resistance induce transcription of the hfgl2 gene dependent on the transcription factor Ets.
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Affiliation(s)
- Weina Li
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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2
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He W, Liu W, Chew CS, Baker SS, Baker RD, Forte JG, Zhu L. Acid secretion-associated translocation of KCNJ15 in gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 2011; 301:G591-600. [PMID: 21719736 PMCID: PMC3191558 DOI: 10.1152/ajpgi.00460.2010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Potassium ions are required for gastric acid secretion. Several potassium channels have been implicated in providing K(+) at the apical membrane of parietal cells. In examining the mRNA expression levels between gastric mucosa and liver tissue, KCNJ15 stood out as the most highly specific K(+) channel in the gastric mucosa. Western blot analysis confirmed that KCNJ15 is abundant in the stomach. Immunofluorescence staining of isolated gastric glands indicated that KCNJ15 was expressed in parietal cells and chief cells, but not in mucous neck cells. In resting parietal cells, KCNJ15 was mainly found in puncta throughout the cytoplasm but was distinct from H(+)-K(+)-ATPase. Upon stimulation, KCNJ15 and H(+)-K(+)-ATPase become colocalized on the apical membranes, as suggested by immunofluorescence staining. Western blot analysis of the resting and the stimulated membrane fractions confirmed this observation. From nonsecreting preparations, KCNJ15-containing vesicles sedimented after a 4-h centrifugation at 100,000 g, but not after a 30-min spin, which did sediment most of the H(+)-K(+)-ATPase-containing tubulovesicles. Most of the KCNJ15 containing small vesicle population was depleted upon stimulation of parietal cells, as indicated by the fact that the KCNJ15 signal was shifted to a large membrane fraction that sedimented at 4,000 g. Our results demonstrate that, in nonsecreting parietal cells, KCNJ15 is stored in vesicles distinct from the H(+)-K(+)-ATPase-enriched tubulovesicles. Furthermore, upon stimulation, KCNJ15 and H(+)-K(+)-ATPase both translocate to the apical membrane for active acid secretion. Thus KCNJ15 can be added to the family of apical K(+) channels in gastric parietal cells.
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Affiliation(s)
- Wenjun He
- 1Digestive Diseases and Nutrition Center, Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York;
| | - Wensheng Liu
- 1Digestive Diseases and Nutrition Center, Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York;
| | - Catherine S. Chew
- 2Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia; and
| | - Susan S. Baker
- 1Digestive Diseases and Nutrition Center, Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York;
| | - Robert D. Baker
- 1Digestive Diseases and Nutrition Center, Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York;
| | - John G. Forte
- 3Department of Molecular and Cell Biology, University of California, Berkeley, California
| | - Lixin Zhu
- 1Digestive Diseases and Nutrition Center, Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York;
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Hakeem L, Thomson G, McCleary E, Bhattacharyya D, Banerjee I. Prevalence and Immunization Status of Hepatitis B Virus in the HIV Cohort in Fife, Scotland. J Clin Med Res 2010; 2:34-8. [PMID: 22457699 PMCID: PMC3299173 DOI: 10.4021/jocmr2009.12.1282] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2009] [Indexed: 12/20/2022] Open
Abstract
Background Routes of transmission of hepatitis B virus (HBV)/HIV infections are similar and there is a significant rate of co-infection in patients. A study was recently carried out in NHS Fife, Scotland from February 2007 - February 2008 to estimate the prevalence of HBV/HIV co-infection, occult HBV infection and immunisation status against HBV in a cohort of patients with HIV attending the departments of infectious diseases and genitourinary medicine. Methods Case notes were reviewed retrospectively (n = 70). Details on patient demographics, risk category, nadir/current CD4 count, HIV viral load and vaccination history were analysed. HBV markers (HBsAg/anti-HBs/anti-HBc/HBV DNA) and alanine transaminase (ALT) levels were tested prospectively if these tests had not been carried out in the previous 12 months. Results and Conclusion Prevalence of HBV/HIV co-infection was 5.6% of which 2.8% of patients had occult infection and 22.9% had evidence of previous exposure. Although HBV is preventable by vaccination, only 24.2% of patients had been vaccinated against it. Improvements could therefore be made in the field of prevention with vaccination and monitoring the immune response in this cohort. Keywords Prevalence; Immunization status; Hepatitis B Virus; HIV
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Affiliation(s)
- Lukman Hakeem
- Infectious Diseases Unit, Victoria Hospital (NHS Fife), Kirkcaldy, Fife, Scotland, UK
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Zhang JC, Nie QH. New antiviral choice for chronic hepatitis B: tenofovir disoproxil fumarate. Shijie Huaren Xiaohua Zazhi 2008; 16:2679-2688. [DOI: 10.11569/wcjd.v16.i24.2679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2. TDF is licensed by American Food and Drug Administration (FDA) in 2001 for the treatment of HIV infection. TDF is currently one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection. Its efficacy, favorable toxicity profile, and convenient dosing have made this drug one of the most popular first-line treatment. Numerous studies have demonstrated the use of TDF in the treatment of HIV infection. It also has been shown to be effective in HIV/HBV coinfected patients and in patients with wild-type and lamivudine-resistant strains. Accumulating evidence suggests that TDF is more potent in suppressing HBV replication. In this review, we summarize the study progress of TDF in treating HBV infection.
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Combination therapy of lamivudine and adefovir in Japanese patients with chronic hepatitis B. Hepatol Int 2008; 2:361-9. [PMID: 19669266 PMCID: PMC2716896 DOI: 10.1007/s12072-008-9081-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 04/27/2008] [Indexed: 12/22/2022]
Abstract
PURPOSE This study aimed to clarify the long-term efficacy of the lamivudine treatment in Japanese patients with chronic hepatitis B either with or without lamivudine resistance or with or without adefovir add-on treatment. METHODS We followed 110 patients who received lamivudine for more than 12 months, including 67 hepatitis B e antigen (HBeAg)-positive and 43 HBeAg-negative patients. RESULTS The median follow-up after the onset of lamivudine was 48 (range = 12-86) months. In all the patients with or without lamivudine resistance, the level of alanine aminotransferase (ALT) normalization decreased from 70.0% at 1 year to 36.4% at 5 years and the loss of serum HBV DNA level decreased from 72.7% at 1 year to 31.8% at 5 years. Sixty patients (54.6%) developed a lamivudine-resistant mutation, and this occurrence was more frequently observed in those who were HBeAg-positive (P < 0.01), those with a low level of ALT (P < 0.05), and those with a high level of serum HBV DNA (P < 0.01). Thirty-six of 60 patients received adefovir in addition to lamivudine to treat breakthrough hepatitis. A Cox proportional hazards model analysis revealed the level of baseline HBV DNA to be the best predictive factor for the virus recrudescence (risk ratio = 0.466, 95% confidence interval [CI]: 0.246-0.842, P = 0.011) and the breakthrough hepatitis (risk ratio = 0.444, 95% CI: 0.218-0.879, P = 0.019). We carefully monitored the efficacy of this treatment both in patients who received adefovir and in those who did not since the beginning of the lamivudine treatment. The normalization level of ALT was 61.4% at 5 years and the loss of serum HBV DNA was 61.4% at 5 years since lamivudine was started. A histologic improvement was observed in patients with ALT levels less than two times the upper limit of normal at the time of a second liver biopsy. CONCLUSIONS Although the efficacy of lamivudine is limited because of breakthrough hepatitis, adefovir was used as a salvage treatment of patients with lamivudine-resistant chronic hepatitis B. In addition, lamivudine was used for the treatment of Japanese patients with chronic hepatitis B with or without lamivudine resistance, and was found to be useful regarding the long-term virologic and biochemical responses.
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Abstract
HIV and hepatitis B virus (HBV) infection share transmission patterns and risk factors; therefore, it is not surprising that the prevalence of chronic HBV infection is elevated among HIV-infected persons. HBV does not significantly affect the course of HIV disease, but HIV does alter the course of HBV. HIV-infected persons are less likely to clear acute HBV infection spontaneously, and HIV/HBV-coinfected persons face a higher risk of liver-related death than those monoinfected with either virus. The immune restoration associated with highly active antiretroviral therapy (HAART) can improve control of HBV replication but can also lead to increased immune-mediated liver injury. On balance, use of HAART before severe immunosuppression develops may be beneficial. Still, the complexity of HBV, HIV, and HAART interactions must be evaluated for each individual. There is a dearth of high-quality evidence about management of coinfected patients. A recent consensus conference has issued recommendations. HBV DNA thresholds for starting anti-HBV therapy are the same in coinfected and HBV-monoinfected patients. Continuing drugs with anti-HBV activity is important, because stopping such therapy has been associated with HBV reactivation. Development of resistance is a risk with the long-term maintenance therapy required in most patients.
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Affiliation(s)
- Yves Benhamou
- Service d'Hépato-Gastro-Entérologie, Hospitalier Pitié-Salpêtrière, Paris, France.
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Abstract
Chronic hepatitis B virus infection afflicts 400 million people worldwide and untreated will progress to cirrhosis in 15-40% of individuals, with an associated increased risk for the development of hepatocellular carcinoma. The 'inactive carrier state' carries a benign prognosis with a very low risk of cirrhosis or hepatocellular carcinoma. However, the hepatitis B e antigen (HBeAg)-positive chronic hepatitis state is an active disease state with increased risk for progressing to cirrhosis and hepatocellular carcinoma. The HBeAg-negative mutant variety of chronic hepatitis B has been associated with a higher incidence of cirrhosis at initial presentation and more frequent progression to hepatocellular carcinoma compared with the wild-type hepatitis B. Five medications are currently approved by the US FDA for the treatment of chronic hepatitis B: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir and peginterferon-alpha-2a. Interferon-alpha therapy has been shown to increase the rate of HBeAg and hepatitis B DNA loss with a small chance of hepatitis B surface antigen loss, but has significant adverse effects and is ineffective against the HBeAg-negative mutant. Lamivudine is a safely used, orally administered drug with good efficacy, but is associated with the development of a lamivudine-resistant (Lam-R) mutant in a large proportion of patients after long-term therapy. High relapse rates after lamivudine therapy make this medication less effective in the HBeAg-negative mutant also. Adefovir dipivoxil is a safely used, orally administered drug, which is effective against the Lam-R mutant. Adefovir dipivoxil is effective against the wild-type and HBeAg-negative hepatitis B and has a very low incidence of resistance development. Entecavir is a highly potent and selective new oral drug against hepatitis B. It has demonstrated no resistance development in treatment-naive patients, but a low incidence of resistance in patients infected with prior Lam-R mutants. Peginterferon-alpha-2a is administered once weekly and has improved efficacy compared with standard interferon-alpha and lamivudine. However, it has a similar adverse-effect profile to standard interferon-alpha. Pharmacoeconomic studies have demonstrated a cost benefit in treating chronic hepatitis B patients compared with no therapy. However, results have been conflicting, with earlier studies showing a cost advantage of lamivudine over interferon-alpha and a more recent, comprehensive study favouring interferon-alpha monotherapy in HBeAg-negative patients and adefovir dipivoxil 'salvage' after lamivudine resistance development in HBeAg-positive patients.
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Affiliation(s)
- Steven-Huy B Han
- David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7302, USA.
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8
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Matthews GV, Cooper DA, Dore GJ. Improvements in Parameters of End-Stage Liver Disease in Patients with HIV/HBV-related Cirrhosis Treated with Tenofovir. Antivir Ther 2007. [DOI: 10.1177/135965350701200116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background Mortality related to end-stage liver disease is increasing in HIV/hepatitis B virus (HBV)-coinfected patients and effective treatment options are limited. Tenofovir is now widely used in HIV/HBV coinfection and results in significant HBV suppression, in both patients with and patients without lamivudine resistance. The safety and efficacy of tenofovir in HIV/HBV cirrhosis has not been previously described. Methods Seven cirrhotic HIV/HBV patients treated with tenofovir were identified within the HIV clinic. Parameters of hepatic function, CD4+ T-cell counts, HBV DNA levels and Child-Pugh Class (C-P-C) were determined before and after addition of tenofovir. All patients had prior lamivudine experience with a median baseline HBV DNA of 6.23x107 copies/ml. Results Four of seven patients were C-P-C -A and hepatitis ‘e’ antigen (HBeAG) was positive in 4/7 patients. After a median duration of tenofovir of 28 months, all laboratory parameters improved, with significant changes in albumin and prothrombin (PT) (median pre-/post-tenofovir: alanine aminotransferase 63/39; bilirubin 26/18; albumin 39/44, P=0.028; PT 17.5/15, P=0.018). All three patients with C-P-C -B or -C improved to C-P-C -A, which for one patient enabled removal from the liver transplant waiting list. Three patients lost HBeAG with two anti-HBe seroconversions. Median HBV DNA was suppressed to <35 copies/ml. Conclusions This study demonstrates that tenofovir can produce HBV viral suppression, HBeAg seroconversion and improvement in markers of hepatic function in HIV/HBV-coinfected patients with cirrhosis. The potential reversal of end-stage liver disease may provide an important survival benefit in this population.
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Affiliation(s)
- Gail V Matthews
- HIV/Immunology/Infectious Diseases Unit, St Vincent's Hospital, Sydney, Australia
- Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
| | - David A Cooper
- HIV/Immunology/Infectious Diseases Unit, St Vincent's Hospital, Sydney, Australia
- Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
| | - Gregory J Dore
- HIV/Immunology/Infectious Diseases Unit, St Vincent's Hospital, Sydney, Australia
- Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
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9
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Cadranel JF. [Clinical consequences of resistance to analogue antiviral drugs in the treatment of chronic hepatitis B]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2006; 30:3S12-3S16. [PMID: 17075489 DOI: 10.1016/s0399-8320(06)73524-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- Jean-François Cadranel
- Service d'Hépato-Gastroenterologie et de Diabétologie, Centre Hospitalier Laënnec BP 72, 60109 Creil Cedex, France.
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10
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Abstract
HIV-infected individuals have myriad causes of hepatotoxicity that range from mild hepatitis to significant liver failure with its associated morbidity and mortality, especially in the setting of chronic viral hepatitis (HCV and HBV). Immune restoration by HAART therapy can contribute liver-related toxicity in HIV-coinfected patients. Clinicians need to be aware of this problem and individualize management in this challenging clinical scenario. Avoidance of potentially hepatotoxic agents or close monitoring during treatment of HIV may prevent liver failure in patients who have HIV. Furthermore, vaccination against hepatitis A virus and HBV in nonimmune HIV individuals may prevent acquisition of hepatitis A virus and HBV infections in patients who have HIV. Finally, treatment of HIV, and, if appropriate, treatment of those who are coinfected with HCV and HBV with close monitoring, may improve the outcome of patients who have HIV and are at risk fo r significant hepatotoxicity during treatment from immune restoration or hypersensitivity reactions.
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Affiliation(s)
- Homayon Sidiq
- St. Luke's Episcopal Hospital Center for Liver Disease, 6620 Main St. 15051, Houston, TX 77301, USA
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11
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Abstract
HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.
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Affiliation(s)
- Massimo Puoti
- Clinica di Malattie Infettive e Tropicali, AO Spedali Civili, Università di Brescia, P.zzle Spedali Civili 1, I 25123 Brescia, Italy.
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Abstract
For the treatment of HBV/HIV-co-infection, study data on interferon-based therapy are very limited and insufficient to draw any specific conclusions. In contrast, data on HBV-polymerase inhibitors (lamivudine, adefovir, tenofovir) are available from controlled trials. Lamivudine is well tolerated and safe, however, development of HBV-resistance is frequent. Adefovir has a nephrotoxic potential and may at least theoretically induce antiretroviral resistance in HBV/HIV-patients treated with adefovir. Tenofovir has gastrointestinal side effects, is associated with hypophospatemia, which has not induced serious osteopenia so far and may have a nephrotoxic potential. For HCV/HIV-co-infection pegylated interferon alpha plus ribavirin is standard of care. Flu-like symptoms, fatigue and depressive mood changes are frequent. In patients with a history of neurotic or minor depression initiation of treatment with antidepressants before the start of interferon-based therapy should be considered. Weight loss may be pronounced in individual cases. A marked decrease in absolute, but not relative CD4 +/- cells is the rule, but no relevant increase in opportunistic infection was observed, and anaemia (<10 g/dl) is reported in up to 30% of patients. Neutropenia (< 1,000 cells/microl) is observed in up to 50% of the patients. Adverse events specific to the HCV/HIV-patient population as compared to HCV-mono-infected patients are the occurrence of hyperlactataemia/lactic acidosis and hepatic decompensation.
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Affiliation(s)
- Stefan Mauss
- Center for HIV and Hepatogastroenterology, Grafenberger Allee 128a, 40237 Duesseldorf, Germany.
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Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, Rozenbaum W, Le Teuff G, Trylesinski A, Piketty C. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology 2006; 43:548-55. [PMID: 16496322 DOI: 10.1002/hep.21055] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) has shown in vitro activity against both HIV and hepatitis B virus (HBV). We retrospectively evaluated the efficacy of TDF (300 mg/d), administered as a part of anti-retroviral therapy, in a large cohort of HIV/HBV-coinfected patients. Sixty-five HIV/HBV-coinfected patients who received TDF for at least 6 months with serum HBV DNA levels above 2.3 log10 copies/mL at TDF initiation and who had stored serum samples before and during TDF therapy were included. Serum HBV DNA was measured on stored samples. The median follow-up period was 12 (Q1-Q3: 8-17) months. Serum hepatitis B e antigen (HBeAg) was positive in 54 patients (83.1%). Fifty-two patients (80.0%) were receiving lamivudine (LAM) (150 mg twice a day), and 68.8% had documented LAM resistance at baseline. Among HBeAg-positive patients, the median reduction from baseline (8.17; Q1-Q3 = 7.30-8.30 log10 copies/mL) of serum HBV DNA was 4.56 log10 copies/mL (Q1-Q3 = 3.33-5.55) (P < .0001). In HBeAg-negative patients, serum HBV DNA decline from baseline (4.83; Q1-Q3 = 2.69-6.40 log10 copies/mL) was 2.53 log10 copies/mL (Q1-Q3 = 0.39-4.10). At the end of the study, HBV DNA became undetectable in 29.6% and 81.6% of the HBeAg-positive and HBeAg-negative patients, respectively. Serum HBeAg became negative in 4 patients, 2 of whom acquired serum hepatitis B e antibody. In conclusion, this retrospective analysis demonstrates the efficacy of TDF against wild-type, presumed precore mutants and LAM-resistant HBV when used as a part of anti-retroviral therapy in HIV-coinfected patients.
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Affiliation(s)
- Yves Benhamou
- Service d'Hépato-gastroentérologie, Hôpital Pitié Salpetrière, Paris, France.
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Benhamou Y, Thibault V, Vig P, Calvez V, Marcelin AG, Fievet MH, Currie G, Chang CG, Biao L, Xiong S, Brosgart C, Poynard T. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 2006; 44:62-7. [PMID: 16274835 DOI: 10.1016/j.jhep.2005.08.020] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Revised: 07/21/2005] [Accepted: 08/05/2005] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Adefovir dipivoxil (10 mg once-daily) was added to antiretroviral therapy including lamivudine in 35 HIV/HBV co-infected patients. METHODS Parameters evaluated included alanine aminotransferase (ALT), HBV DNA and serological markers, HIV-1 RNA, and CD4+ cell count. RESULTS Twenty-nine patients (83%) completed 144 weeks. Serum HBV DNA declined from a baseline 9.76 log10 copies/mL (median) to 4.68, 5.24, and 5.90 log10 copies/mL at weeks 48, 96, and 144, respectively (P<0.0001 at all time points). Seven patients (25%) achieved HBV DNA<2.3 log10 copies/mL. No adefovir-associated resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were detected. ALT declined from 81 IU/L (median) at baseline by -16.0, -44.5, and -46.0 IU/L at week 48, 96 and 144, respectively (P=<0.05, respectively), and normalized in 71% of patients (20 of 28) by week 144. Two patients developed antibodies against HB 'e' antigen by week 48. No serious adverse events related to adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable. CONCLUSIONS Treatment with adefovir dipivoxil for 144 weeks was well tolerated and resulted in significant and sustained reductions in HBV DNA and ALT in HIV/HBV co-infected patients. Efficacy increased with treatment duration, with no loss of viral suppression.
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Affiliation(s)
- Yves Benhamou
- Groupe Hospitalier Pitie-Salpetriere, Service de d'Hépato-Gastroentérologie, Paris, France.
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15
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Eckert V, Struff WG. Hepatitis B: Where Are We Today? Transfus Med Hemother 2006. [DOI: 10.1159/000093298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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16
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Brook MG, Gilson R, Wilkins E. BHIVA guidelines on HIV and chronic hepatitis: coinfection with HIV and hepatitis B virus infection (2005). HIV Med 2005; 6 Suppl 2:84-95. [PMID: 16011538 DOI: 10.1111/j.1468-1293.2005.00301.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- M G Brook
- Central Middlesex Hospital, London, UK.
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Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S, Klesczewski KS, Thiry A, Rose RE, Colonno RJ, Hindes RG. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology 2005; 129:1198-209. [PMID: 16230074 DOI: 10.1053/j.gastro.2005.06.055] [Citation(s) in RCA: 220] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2004] [Accepted: 06/16/2005] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. METHODS Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for > or =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. RESULTS At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). CONCLUSIONS In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.
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Younger HM, Bathgate AJ, Hayes PC. Review article: Nucleoside analogues for the treatment of chronic hepatitis B. Aliment Pharmacol Ther 2004; 20:1211-30. [PMID: 15606384 DOI: 10.1111/j.1365-2036.2004.02211.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Current accepted treatment for chronic hepatitis B uses either the immunomodulator interferon alpha or nucleoside analogues lamivudine or adefovir. Interferon has side effects which mean it is often poorly tolerated. Long-term use of lamivudine is associated with increasing viral resistance for each year it is taken and the rebound viraemia that can occur when the drug is stopped is also of concern to many. Adefovir appears to have less of the resistance issues of lamivudine but is still a relatively new drug and at present its use is principally limited to patients with lamivudine-resistant disease. A number of other nucleoside analogues are currently being developed with some now at the stage of early clinical trials. A proportion share the significant resistance problems of lamivudine but many appear to have more potent anti-viral effect than the drugs currently available. If some of these newer anti-viral agents are approved for use in chronic hepatitis B, the potential for prolonged suppression of hepatitis B virus replication with resultant stabilization or improvement in liver disease may be achieved.
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Affiliation(s)
- H M Younger
- Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
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Abstract
Patients who are chronically infected with the hepatitis B virus are at an increased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma. Therapeutic intervention offers the only means of interrupting this progression. Currently there are three licensed agents for the treatment of chronic hepatitis B virus infection. These are interferon-alpha, an immunomodulator, and two synthetic nucleos(t)ide analogs, namely lamivudine (Epivir, GlaxoSmithKline) and adefovir dipivoxil (Hepsera, Gilead Sciences). This review aims to summarize current experience with these drugs in the treatment and management of patients with chronic hepatitis B virus infection, their efficacy, and current problems of drug resistance. An outline of future treatment perspectives is also included.
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Affiliation(s)
- Peter Karayiannis
- Imperial College London, Department of Medicine A, Hepatology Section, Faculty of Medicine, St Mary's Campus, South Wharf Road, London, W2 1NY, UK.
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20
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Benhamou Y, Bonyhay L. Treatment of hepatitis B virus infection in patients coinfected with HIV. Gastroenterol Clin North Am 2004; 33:617-27, x. [PMID: 15324947 DOI: 10.1016/j.gtc.2004.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
This article highlights research into which treatments may be most effective for people with both hepatitis B virus infection and HIV. Studies from the era before highly active antiretroviral therapy and more recent studies are included.
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Affiliation(s)
- Yves Benhamou
- Service d'Hépato-Gastroentérologie, Hôpital Pitié-Salpêtrière, 27 Boulevard de l'Hôpital, 75013 Paris, France.
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21
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Santos EA, Sucupira MVF, Arabe J, Gomes SA. Hepatitis B virus variants in an HIV-HBV co-infected patient at different periods of antiretroviral treatment with and without lamivudine. BMC Infect Dis 2004; 4:29. [PMID: 15339340 PMCID: PMC516776 DOI: 10.1186/1471-2334-4-29] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2004] [Accepted: 08/31/2004] [Indexed: 02/07/2023] Open
Abstract
Background Lamivudine inhibits replication of both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and is commonly used as part of antiretroviral therapy. The main limitation in the use of lamivudine is resistant mutation selection. Most of these mutations affect the YMDD motif of the HBV DNA polymerase. The resistance occurs through M550V or M550I aminoacid replacements. The M550V variation may be accompanied by L526M mutation, notably in HIV-HBV co-infected patients. The aim of this study was to investigate mutations associated with lamivudine resistance in a hemodialysis patient chronically co-infected with HIV-1 and HBV, who was submitted to several antiretroviral treatments. Methods HBV isolates derived from three blood samples collected at different times of antiretroviral therapies with and without lamivudine, were titred and submitted to nucleotide sequencing. Results HBV isolate derived from a sample collected in 1999 during an antiretroviral treatment with lamivudine showed the lamivudine resistant double mutation (L526M, M550V). However, no mutation associated with lamivudine resistance was observed in the HBV genome derived from the sample collected during a period of treatment without lamivudine (2001). After reinstitution of lamivudine (2002), the predominant HBV population exhibited a rare triple mutation (V519L, L526M, M550V), which has previously been associated with an in vitro reduction of virus antigenicity (escape mutant). HBV DNA was detected at high levels (108–109 copies/ml) in the three blood samples. Conclusions Reintroduction of lamivudine as part of antiretroviral treatment in a patient who had developed lamivudine resistant HBV strains favored the predominance of an HBV isolate with reduced antigenicity. The absence of hepatitis acute exacerbation in this patient may be correlated to the absence of significant variations of the viral load, which was independent of the presence of mutations in the HBV DNA polymerase.
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Affiliation(s)
- Eneida A Santos
- Department of Virology, Oswaldo Cruz Institute, Rio de Janeiro, RJ 21045-900, Brazil
| | - Michel VF Sucupira
- Department of Virology, Oswaldo Cruz Institute, Rio de Janeiro, RJ 21045-900, Brazil
| | - Juçara Arabe
- Gaffrée and Guinle University Hospital, Rio de Janeiro, RJ 20270-004, Brazil
| | - Selma A Gomes
- Department of Virology, Oswaldo Cruz Institute, Rio de Janeiro, RJ 21045-900, Brazil
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22
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Puoti M, Cozzi-Lepri A, Ancarani F, Bruno R, Ambu S, Ferraro T, Tundo P, Santantonio T, Toti M, Bonasso M, Monforte AD, Ancarani F, Antonucci G, Bonasso M, Bruno R, Cozzi-Lepri A, Monforte AD, Luca AD, Galli M, Gennero L, Girardi E, Lipani F, Marino N, Milazzo L, Morsica G, Narciso P, Pizzaferri P, Puoti M, Santantonio T, Verucchi G, Montroni M, Scalise G, Zoli A, Prete MSD, Tirelli U, Di Gennaro G, Pastore G, Ladisa N, Minafra G, Suter F, Arici C, Chiodo F, Colangeli V, Fiorini C, Coronado O, Carosi G, Cadeo GP, Castelli F, Minardi C, Vangi D, Rizzardini G, Migliorino G, Manconi PE, Piano P, Ferraro T, Scerbo A, Pizzigallo E, D'Alessandro M, Santoro D, Pusterla L, Carnevale G, Galloni D, Viganò P, Mena M, Ghinelli F, Sighinolfi L, Leoncini F, Mazzotta F, Pozzi M, Lo Caputo S, Angarano G, Grisorio B, Ferrara S, Grima P, Tundo P, Pagano G, Piersantelli N, Alessandrini A, Piscopo R, Toti M, Chigiotti S, Soscia F, Tacconi L, Orani A, Perini P, Scasso A, Vincenti A, Chiodera F, Castelli P, Scalzini A, Fibbia G, Moroni M, Lazzarin A, Cargnel A, Vigevani GM, Caggese L, d'Arminio Monforte A, Repetto D, Novati R, Galli A, Merli S, Pastecchia C, Moioli MC, Esposito R, Mussini C, Abrescia N, Chirianni A, Izzo C, Piazza M, De Marco M, Montesarchio V, Manzillo E, Graf M, Colomba A, Abbadessa V, Prestileo T, Mancuso S, Ferrari C, Pizzaferri P, Filice G, Minoli L, Bruno R, Novati S, Balzelli F, Loso K, Petrelli E, Cioppi A, Alberici F, Ruggieri A, Menichetti F, Martinelli C, De Stefano C, La Gala A, Ballardini G, Briganti E, Magnani G, Ursitti MA, Arlotti M, Ortolani P, Ortona L, Dianzani F, Ippolito G, Antinori A, Antonucci G, D'Elia S, Narciso P, Petrosillo N, Vullo V, De Luca A, Del Forno L, Zaccarelli M, Acinapura R, De Longis P, Ciardi M, D'Offizi G, Trotta MP, Noto P, Lichtner M, Capobianchi MR, Girardi E, Pezzotti P, Rezza G, Mura MS, Mannazzu M, Caramello P, Sinicco A, Soranzo ML, Gennero L, Sciandra M, Bonasso M, Grossi PA, Basilico C, Poggio A, Bottari G, Raise E, Pasquinucci S, De Lalla F, Tositti G, Resta F, Chimienti A, Cozzi-Lepri A. The Management of Hepatitis B Virus/HIV-1 Co-Infected Patients Starting Their First Haart Regimen. Treating Two Infections for the Price of One Drug? Antivir Ther 2004. [DOI: 10.1177/135965350400900506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We examined the impact of a lamivudine-containing highly active antiretroviral therapy (HAART) regimen on 164 hepatitis B virus/HIV co-infected individuals starting their first HAART. Lamivudine-treated patients (accounting for 73% of the study population) showed a significantly lower level of alanine aminotransferase over follow-up [–81.1 mU/ml mean difference; 95% confidence intervals (95% CI): –30.3; –131.7, P=0.003] and a significantly reduced risk of liver-related morbidity/mortality [Relative hazard (RH)=0.07; 95% CI: 0.01–0.38, P=0.002] than those starting a lamivudine sparing-regimen.
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Affiliation(s)
| | - Massimo Puoti
- Institute of Infectious and Tropical Diseases, Spedali Civili, University of Brescia, Brescia, Italy
| | - Alessandro Cozzi-Lepri
- Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK
| | - Fausto Ancarani
- Institute of Infectious Diseases and Public Health, Umberto I Hospital, University of Ancona, Ancona, Italy
| | - Raffaele Bruno
- Institute of Infectious and Tropical Diseases, IRCCS S Matteo, University of Pavia, Pavia, Italy
| | - Silvia Ambu
- Department of Infectious Diseases, Azienda Ospedaliera Careggi, Firenze, Italy
| | - Teresa Ferraro
- Department of Infectious Diseases, Ospedale A Puglise, Catanzaro, Italy
| | - Paolo Tundo
- Department of Infectious Diseases, Ospedale Santa Caterina Novella, Galatina (Lecce), Italy
| | | | - Mario Toti
- Department of Infectious Diseases, Ospedale di Grosseto, Grosseto, Italy
| | - Marino Bonasso
- Department of Infectious Diseases, Ospedale ‘Amedeo Savoia’, Torino, Italy
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Kagawa T, Watanabe N, Kanouda H, Takayama I, Shiba T, Kanai T, Kawazoe K, Takashimizu S, Kumaki N, Shimamura K, Matsuzaki S, Mine T. Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant. World J Gastroenterol 2004; 10:1686-7. [PMID: 15162553 PMCID: PMC4572782 DOI: 10.3748/wjg.v10.i11.1686] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We report a case of fatal liver failure due to reactivation of lamivudine-resistant HBV. A 53-year-old man was followed since 1998 for HBV-related chronic hepatitis. Serum HBV-DNA was 150 MEq/mL (branched DNA signal amplification assay) and ALT levels fluctuated between 50-200 IU/L with no clinical signs of liver cirrhosis. Lamivudine (100 mg/d) was started in May 2001 and serum HBV-DNA subsequently decreased below undetectable levels. In May 2002, serum HBV-DNA had increased to 410 MEq/mL, along with ALT flare (226 IU/L). The YMDD motif in the DNA polymerase gene had been replaced by YIDD. Lamivudine was continued and ALT spontaneously decreased to the former levels. On Oct 3 the patient presenting with general fatigue, nausea and jaundice was admitted to our hospital. The laboratory data revealed HBV reactivation and liver failure (ALT: 1828 IU/L, total bilirubin: 10 mg/dL, and prothrombin INR: 3.24). For religious reasons, the patient and his family refused blood transfusion, plasma exchange and liver transplantation. The patient died 10 d after admission. The autopsy revealed remarkable liver atrophy.
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Affiliation(s)
- Tatehiro Kagawa
- Department of Internal Medicine, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193, Japan.
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24
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Benhamou Y. Antiretroviral therapy and HIV/hepatitis B virus coinfection. Clin Infect Dis 2004; 38 Suppl 2:S98-103. [PMID: 14986281 DOI: 10.1086/381451] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Among human immunodeficiency virus (HIV)-infected individuals, the prevalence of hepatitis B surface antigen (HBsAg) seropositivity is approximately 10-fold higher than in the general population. HIV/hepatitis B virus (HBV)-coinfected patients have an increased risk of cirrhosis and liver-disease-related death. The strategy and management of anti-HBV therapy in HIV-infected persons must take into consideration both viral infections. Among HIV/HBV-coinfected patients, lamivudine promptly inhibits HBV replication. The emergence of resistance to lamivudine has been documented in HBV strains. Adefovir has been shown to be effective in the treatment of lamivudine-resistant HBV in HIV/HBV-coinfected patients. Tenofovir has recently been shown to have significant activity against both HIV and HBV. HBsAg seropositivity has been identified as an independent predictor of highly active antiretroviral therapy-related hepatotoxicity. However, further research is needed to determine the exact role of HBV and the mechanisms involved in antiretroviral-associated hepatotoxicity in HBV/HIV-coinfected patients.
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Affiliation(s)
- Yves Benhamou
- Service d'Hepato-Gastroenterologie, Hopital Pitie-Salpetriere, Paris, France.
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25
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Benhamou Y, Poynard T. Treatment of chronic hepatitis B virus infection in patients co-infected with human immunodeficiency virus. J Hepatol 2004; 39 Suppl 1:S194-9. [PMID: 14708703 DOI: 10.1016/s0168-8278(03)00321-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Yves Benhamou
- Service d'Héparo-Gastroentérologie, Hôpital Pitié-Salpêtrière, 27 Boulevard de l'Hôpital, 75013 Paris, France.
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26
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Zehender G, De Maddalena C, Milazzo L, Piazza M, Galli M, Tanzi E, Bruno R. Hepatitis B virus genotype distribution in HIV-1 coinfected patients. Gastroenterology 2003; 125:1559-60; author reply 1660. [PMID: 14628817 DOI: 10.1016/j.gastro.2003.03.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Brook MG, Gilson R, Wilkins EL. BHIVA Guidelines: coinfection with HIV and Chronic hepatitis B virus. HIV Med 2003; 4 Suppl 1:42-51. [PMID: 14511247 DOI: 10.1046/j.1468-1293.4.s1.1.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- M G Brook
- Central Middlesex Hospital, London, UK.
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28
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Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, Brosgart C, Colledge D, Edwards R, Ayres A, Bartholomeusz A, Locarnini S. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003; 125:292-7. [PMID: 12891527 DOI: 10.1016/s0016-5085(03)00939-9] [Citation(s) in RCA: 474] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. METHODS HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. RESULTS Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log(10) decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir. CONCLUSIONS The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.
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Affiliation(s)
- Peter Angus
- Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia.
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29
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Cooley L, Ayres A, Bartholomeusz A, Lewin S, Crowe S, Mijch A, Locarnini S, Sasadeusz J. Prevalence and characterization of lamivudine-resistant hepatitis B virus mutations in HIV-HBV co-infected individuals. AIDS 2003; 17:1649-57. [PMID: 12853747 DOI: 10.1097/00002030-200307250-00009] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV. DESIGN Retrospective cross-sectional study. METHODS Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive samples underwent sequencing of HBV polymerase, basal core promoter and precore regions. RESULTS Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 individuals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a 'vaccine escape' mutant of HBV. CONCLUSION Genotypic HBV lamivudine resistance was found in 39% of HIV-HBV co-infected individuals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated individuals.
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Affiliation(s)
- Louise Cooley
- Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
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Núñez M, Pérez-Olmeda M, Díaz B, Ríos P, González-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. AIDS 2002; 16:2352-4. [PMID: 12441815 DOI: 10.1097/00002030-200211220-00023] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Treatment of hepatitis B virus (HBV) with lamivudine may not completely suppress viral replication and often fails as a result of lamivudine resistance. Tenofovir is a new HIV inhibitor with further activity against HBV, which was explored in 12 HBV/HIV-co-infected patients with detectable levels of serum HBV-DNA, despite receiving a lamivudine-containing antiretroviral regimen. Lamivudine-resistance mutations were found in HBV from seven patients. HBV-DNA levels dropped a median of 3.78 logs from baseline to 24 weeks. Tenofovir was very effective at reducing HBV-DNA levels in HIV/HBV-co-infected patients carrying either wild-type or lamivudine-resistant viruses.
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Affiliation(s)
- Marina Núñez
- Service of Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain
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31
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Bozkaya H, Yurdaydin C, Bozdayi AM, Erkan O, Karayalcin S, Uzunalimoglu O. Oral ganciclovir for treatment of lamivudine-resistant hepatitis B virus infection: a pilot study. Clin Infect Dis 2002; 35:960-5. [PMID: 12355383 DOI: 10.1086/342907] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2002] [Revised: 06/10/2002] [Indexed: 01/07/2023] Open
Abstract
Although liver disease seems to be stable in most patients who are infected with lamivudine-resistant mutant hepatitis B virus (HBV) in the short term, it may progress to more-advanced disease in some patients. In our pilot study, we investigated the efficacy of oral ganciclovir for the treatment of lamivudine-resistant HBV infection. Six patients infected with lamivudine-resistant HBV (3 patients had decompensated cirrhosis and 3 had chronic active hepatitis without cirrhosis) were included. Ganciclovir was administered at a dosage of 3 g daily for 6 months. Four of 6 patients completed the 6-month treatment period. Two patients with cirrhosis completed only 2 months of ganciclovir treatment because they died of cirrhosis complications. None of the patients had a > or =2-log(10) reduction of HBV DNA and complete alanine aminotransferase normalization at the end of their treatment regimens. In conclusion, 6 months of ganciclovir treatment is not effective for suppression of lamivudine-resistant HBV infection.
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Affiliation(s)
- Hakan Bozkaya
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey.
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