(BQ) Part 2 book Comprehensive textbook of hepatitis B has contents: Hepatitis B in pregnancy, hepatitis B and delta virus coinfection and superinfection, antivirals against hepatitis B virus, new strategies in hepatitis B management,.... and other contents.
Hepatitis B in Pregnancy 16 157 Hepatitis B in Pregnancy Desmond Wai, Kai-Chah Tan INTRODUCTION Chronic hepatitis B is a major cause of morbidity and mortality in many parts of Asia, as prevalence of hepatitis B ranged from to 20% in various parts of Asia It is not uncommon for physicians to encounter pregnant hepatitis B patients in their clinical practice Besides, maternal-fetal transmission is considered the major source of transmission of hepatitis B in Asia Hence, it is important for physicians to be aware of hepatitis B management before, during, and after pregnancy PREPREGNANCY MANAGEMENT Physicians must be aware that none of the antivirals against hepatitis B are classified as FDA pregnancy category A In patients with chronic hepatitis B requiring antiviral therapy, injectables such as interferon, pegylated interferon α-2a and 2b are generally given over a 6–12 months period, while oral antivirals such as nucleoside or nucleotide analogs are often given over prolonged period of up to a few years in duration Therefore, before treating female hepatitis B patients in the reproductive age group, physicians must discuss the potential benefits of antivirals, the possible need for prolonged administration of antivirals, and the insufficient safety data of antivirals during pregnancy with both the patient and the spouse In patients having mild liver disease, it may be better to wait till the patient has completed her family before administering oral antivirals Alternatively, physicians can consider using pegylated interferons as the first line treatment for young female hepatitis B patients as they are given over a defined period of time In patients with severe liver disease and oral antivirals are being administered, it is prudent to ask patients to consider using contraceptives while they are on antiviral treatment WHEN A HEPATITIS B INFECTED PATIENT BECOMES PREGNANT The Advisory Committee on Immunization Practices (AICP), which advises the Center for Disease Control and Prevention (DCD) on the control of vaccinepreventable diseases, recommends that all pregnant women be tested for HBsAg during an early prenatal visit in each pregnancy, irregardless of whether they have 158 Comprehensive Textbook of Hepatitis B been vaccinated or tested previously Many previously undiagnosed hepatitis B cases are discovered by this screening exercise Several case studies from Hong Kong and USA have shown that both maternal and neonatal outcomes in mother with chronic hepatitis B were comparable to non-hepatitis B mothers Among all antivirals against hepatitis B, telbivudine and tenofovir are classified as FDA pregnancy category B drug However, safety data of both of them among pregnant hepatitis B carriers are lacking Lamivudine, though classified as category C, has the longest safety record among pregnant women, and should be used as first-line antiviral agent during pregnancy After delivery, lamivudine can be switched to more potent drugs such as entecavir or tenofovir In a study of 1633 infants who had been exposed to lamivudine in utero during the first trimester of pregnancy, the rate of congenital defects was 2.7%, a rate comparable to that in unexposed pregnant females While some patients may be worried about the lack of safety data of antivirals, the thought of stopping antivirals must be balanced with the risk of withdrawal flares when antivirals are stopped prematurely Other hepatitis B patients whom are not on antiviral treatment should be monitored as per normal, with liver panel and ultrasound scan being tested every months During pregnancy, alkaline phosphatase level may be mildly elevated, and albumin may be slightly depressed, even in the absence of significant liver disease RISKS OF MATERNAL CHILD TRANSMISSION Prior to the introduction of neonatal hepatitis B vaccination, 10% of neonates born to HBsAg+ve/HBeAg-ve mother, and 90% of neonates born to HBsAg+ve/ HBeAg+ve, became hepatitis B carriers Since the introduction of active (intramuscular administration of doses of recombinant hepatitis B vaccine 0.5 microgram within 12 hours of birth, then at and months of age) and passive vaccination (intramuscular administration of hepatitis B immunoglobulin, HBIG, 0.5 ml within 12 hours of birth), the risk of vertical transmission has dropped to 20,000 IU/ml + +/– + + – Active HCV + Occult HBV +,2000 IU/ml – + + – + HBeAg seroconversion and anti-HBsAg formation will be realized Annual HBsAg seroconversion ratio is 2.08% in coinfected patients and 0.43% in HBV monoinfected patients PATTERNS OF HBV AND HCV COINFECTION The subgroups of coinfection are seen on Table 17.1 Acute HBV and HCV Coinfection Mimms and colleagues studied on incidents that have acute HBV and HCV coinfection Their study show that ALT levels are low, determination duration is slow on HBsAg serum and HBs antigen time is short of these patients have advanced chronic HCV The studies made by Alberti and his friends on 30 acute hepatitis patients show that the 30 patients have active HBV+HCV The observed ALT level is high on these patients but inveteracy of HBV and HCV is varied In the acute period, biphasic fluctuations in ALT are observed Feray C and friends studied on 40 patients with diagnose of fulminant hepatitis The observation shows that 12.5% (5 patients) have acute HBV and HCV coinfection and 7.5% (3 patients) have HCV superinfection HCV and Occult HBV Infection Patients having HCV and occult HBV infections have also serious liver diseases In these patients’ conditions, the inflammation is too much, histological activity is high and ALT level is at higher levels A study made on 200 HCV (+) patients show that 33 of them have HBV DNA (+) CLINICAL COURSE IN HBV AND HCV COINFECTION Patients with dual active HBV and HCV coinfection (HBV DNA + and HCV RNA +) progress to cirrhosis and patients decompensed rapidly It is observed HBV and HCV Coinfection 163 that 23 coinfected patients with HBV DNA replication inhibits HCV RNA replication and histological activity increased In a study of 44 acute HBV superinfection case follow-ups, 13 of the patients recovered A comparison made between coinfected and HBV monoinfected patients against progress to cirrhosis and it is found that 24 of the 44 coinfected patients decompensed; of the 24 chronic hepatitis B patients decompensed Another study made to compare between coinfected and HCV monoinfected patients against decompensed ratio of cirrhosis It is found that the decompensed ratio is 90% for coinfected patients while it is 48% for HCV monoinfected patients Coinfected patients have the high risk of progressing HCC Findings of Benvegu and colleagues made on cirrhosis patients showed that 10 years of cumulative HCC progress risk found on coinfected patients is 45%; the 10 years of cumulative HCC progress risk found on patients with cirrhosis related to HCV monoinfection is 28% and the 10 years of cumulative HCC progress risk found on cirrhosis related to HBV is 16% Depending on these results, the USG and AFP follow-ups of HBV and HCV coinfected patients must be in months time interval or less TREATMENT IN HBV AND HCV COINFECTION The treatment criteria of HBV and HCV coinfection is similar to treatment of monoinfected patients Before starting to treatment, it is crucial to identify which virus is dominant The suggested treatments for the active HBV + active HCV infection with HBV DNA (+) and HCV RNA (+) patients are peg interferon + ribavirin or peg interferon + ribavirin + nucleoside/nucleotide analog The suggested treatments for active HCV + inactive HBV infection with HBV DNA (–) and HCV RNA (+) patients are peg interferon + ribavirin The suggested treatments for active HBV + inactive HCV infection with HBV DNA (+) and HCV RNA (–) patients are peg interferon, peg interferon + nucleoside / nucleotide analog or only nucleoside/nucleotide analog In a study, 16 HBV DNA (+) patients were given IFN MU and ribavirin 1200 mg treatment for months patients responded to treatment as 31.3% permanent HBV (excluded genotype lb) virological responses; patient have HBV and HCV clearance; patients have developed HBsAg seroconversion After treatment; the observed HBV DNA positivity ratio is high on IFN responded HCV cases than IFN non-responders HCV patients The studies show that loss of HCV RNA with interferon is 16.7 to 43.8% On the other hand HCV RNA negativity ratio found is 66.7 to 88% Lu and colleagues found the permanent response ratio of interferon + ribavirin treatment of HBV and HCV coinfected patients is 43%; the permanent response ratio found by Hung and his friends is 69% and the permanent response ratio found by Chuang and his friends is 69% Above all, the factors effecting HCV clearance in HCV infected patients are genotype-non 1-b and considered as low viral load before treatment However, in 164 Comprehensive Textbook of Hepatitis B dual infection, there are no meaningful factors to contemplate the HCV clearance In dual infection, combined treatment provides more HCV clearance A study indicated that HBV and HCV dual infected patients and solely HCV patients responded similarly to combined treatment Two separate studies made with standard IFN-α and ribavirin show that there is no sustainable virological response difference on solely HCV infected patients compared to HBV+HCV coinfected patients Nonetheless; after first fall, it is seen that HBV DNA serum levels rebounds, also HBV replication reoccurs on patients having ambiguously low HBV DNA levels CONCLUSION There is still little information and knowledge on HBV and HCV coinfection treatments At present, there is no clear HBV and HCV coinfection treatment suggestion Series of broad case groups with longer follow-ups are needed FURTHER READING Atanasova MV, Haydouchka IA, Zlatev SP, Stoilova YD, Iliev YT, Mateva NG Prevalence of antibodies against hepatitis C virus and hepatitis B coinfection in healthy population in Bulgaria A seroepidemiological study Minerva Gastroenterol Dietol 2004;50:89-96 Chuang WL, Dai CY, Chang WY, Lee LP, Lin ZY, Chen SC, et al Viral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy Antivir Ther 2005;10(1):125-33 Claudia da Silva, Neiva Sellan Lopes Gonỗales, Josiane Silveira Felix Pereira, Cecília Amélia Fazio Escanhoela, Maria Helena Postal Pavan, Fernando Lopes Gonỗales Junior The influence of occult infection with hepatitis B virus on liver histology and response to interferon treatment in chronic hepatitis C patients Braz J Infect Dis 2004;8(6):10.1590/S1413 Liu JY, Chen PJ, Lai MY, et al Ribavirin and interferon is effective for for hepatitis C virus clearence in hepatitis B and C dually infected patients Hepatology 2003;37:568-76 Liu Z, Hou J Hepatitis B virus and hepatitis C virus dual infection.Int J Med Sci 2006;3:57-62 Sagnelli E, Pasquale G, Coppola N, Scaran F Influence of chronic coinfection with hepatitis B and C virus on liver histology Hepatology 2002;36:1285-91 Seth D Crockett, Emmet B Keeffe Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection Annals of Clinical Microbiology and Antimicrobials 2005;4:13doi:10.1186/1476-0711-4-13 Soriano V, Barreiro P, Nuñez M Management of chronic hepatitis B and C in HIVcoinfected patients J Antimicrob Chemother 2006;57(5):815-8 Villa E, Grottola A, Buttafoco P, et al High doses of alpha_interferon are required in chronic hepatitis duo to coinfection with hepatitis b virus and hepatitis C virus long term results of a prospective randomised trial Am J Gastroenterol 2001; 96:2973-7 Hepatitis B and Delta Virus Coinfection and Superinfection 18 165 Hepatitis B and Delta Virus Coinfection and Superinfection Khalid Mumtaz, Saeed S Hamid HISTORY In 1977 a new virus was discovered accidentally by an Italian scientist, named Mario Rizzeto, while studying the liver biopsy from patients with hepatitis B surface antigen (HBsAg) positive The virus was then named as hepatitis delta agent, which evolves into hepatitis delta virus (HDV) Hepatitis ‘D’ is a defective virus HDV infection is closely associated with hepatitis ‘B’ virus (HBV) infection; simultaneous presence of HBV is required for complete virion assembly and secretion As a result individuals with hepatitis D are always dually infected with HDV and HBV VIRION STRUCTURE Hepatitis B virus belongs to the family of hepadnaviruses, which include duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus The complete virion or Dane particle is 42 nm in diameter HBV also produces 22 nm subviral particles in the form of filaments and spheres that are composed of envelope proteins only The HD virion is composed of an outer lipoprotein envelope made of the surface antigen of the HBV (HBsAg) and an inner ribonucleo-protein structure in which the HDV genome resides The HDV genome consists of a single stranded RNA which is folded as a rod-like structure (Fig 18.1) through internal basepairing is complexed with the only HDV-encoded antigen, the HDAg HBV Genome The genome of HBV is a relaxed circular, partially double stranded DNA of approximately 3200 base pairs in length There are four partially overlapping open reading frames (ORFs) encoding the envelope (pre-S/S), core (precore/core), polymerase, and X proteins HBV has been classified into eight genotypes (A to H) based upon an intergroup divergence of 8% or more in the complete nucleotide sequence The clinical significance of the genotypes is still being determined 166 Comprehensive Textbook of Hepatitis B Fig 18.1: HDV Virion: Schematic representation of the hepatitis D virus virion The HD virion comprises an RNA genome, a single HDV encoded antigen, and a lipoprotein envelope provided by HBV HDV Genome The HDV genome is a small RNA molecule (1676 to 1683 nucleotides in size) bearing some structural analogies with plant viroids and virusoids HDV RNA is a single-stranded circle, with a high degree of self-complementarity and G+ C content causing the circle to collapse as a rod-like structure Significant sequence heterogeneity (as high as 39 percent) exists among the different HDV isolates that have been sequenced, and is basis of its classification into three HDV genotypes Hepatitis D Antigen The only antigen associated with HDV, the hepatitis D antigen (HDAg), is a structural component of the virion It consists of a phosphoprotein encoded by an open reading frame (ORF) present on the RNA strand complementary to the RNA genome (antigenomic strand) Approximately 70 molecules of HDAg are complexed with each molecule of HDV RNA to form a ribonucleic core-like structure HBV LIFE CYCLE The replication cycle of HBV begins with attachment of the virion to the hepatocyte membrane The exact mechanisms of virus attachment are not clear but are thought to be mediated through the pre-S1 region of the virion envelope The virion is uncoated in the hepatocyte cytoplasm and the viral genome enters the hepatocyte nucleus Inside the hepatocyte nucleus, synthesis of the plus strand HBV DNA is completed and the viral genome is converted into a covalently closed circular Management of Chronic Hepatitis B in China 321 or matching placebo tablets in a 3:1 ratio for 12 weeks to evaluate the initial antiviral response At week 12, all subjects started open-label ADV 10 mg QD for 28 weeks After this, subjects who received ADV in the first 12 weeks were rerandomized to receive either ADV or placebo in a 2:1 ratio for 12 weeks to evaluate the effect of discontinuing therapy in a subgroup of subjects Subjects who received placebo in the initial 12 weeks continued to receive open-label ADV The one year data showed that there was a significant difference in reduction of HBV DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively, P < 001) Further reductions in serum HBV DNA and increases in the proportion of subjects with HBV DNA undetectable, and ALT normalization were observed in ADV-treated subjects at week 52 (28% with HBV DNA undetectable and 79% with ALT normalization) The study is continuing for an additional years and the years data will be discussed later Entecavir The first Chinese study about entecavir was to evaluate the antiviral efficacy and safety in nucleoside naive Chinese patients with CHB treated with entecavir or lamivudine It was a randomized, double-blind, double-dummy and control design Five hundred and nineteen nucleoside naive CHB patients were treated with daily dose of ETV 0.5 mg (258 patients) or lamivudine 100 mg (261 patients) for at least 52 weeks The primary endpoint was a composite endpoint of HBV DNA × ULN, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively YMDD mutation developed in 70.8% of the patients at years In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with nonvariants One year durability of seroconversion after stopping lamivudine was 80% Adefovir Four hundred and eighty HBeAg-positive CHB subjects were randomized in an initial 52 weeks controlled ADV study and then offered open label ADV treatment for a further 208 weeks Four hundred and eighty subjects were enrolled in the first year study, a total of 474, 456 ,443, 421 and 390 subjects completed the 1st, 2nd, 3rd, 4th, and 5th year study, respectively At the end of each year, samples were analyzed from those subjects with protocol-defined HBV DNA breakthrough (increase > 1.0 log10 copies/ml from nadir) for the rtN236T or rtA181V ADV mutations The cumulative ADV resistance rate was 0% after year, 1.3% after years, 5.4% after years, 10.4% after years and 14.6% after years Data showed that treatment with ADV in Chinese HBeAg-positive CHB subjects for up to years resulted in a cumulative rate of 14.6% (70/480) ADV resistanceassociated mutations with HBV DNA breakthrough At years, the median HBV DNA reduction was 5.5 log10 and the proportion of subjects achieving HBV undetectable, ALT normalization, HBeAg loss and seroconversion were 55%, 77%, 50% and 29% respectively Management of Chronic Hepatitis B in China 323 Entecavir Entecavir has shown superior efficacy over lamivudine in Chinese nucleosidenaïve chronic hepatitis B (CHB) patients over 48-weeks, with continued clinical benefit to 96 weeks A study evaluated the long-term efficacy of entecavir in Chinese patients with CHB who continued entecavir treatment for 144 weeks Patients receiving either entecavir 0.5 mg/day (n = 258) or lamivudine 100 mg/ day (n = 261) entered the initial 96 weeks randomized, double blind, controlled efficacy study Those not achieving consolidated response (HBV DNA