Search Article Keyword  
PubMed Submission Abstract PDF Cited  Click Count: 3957 DownLoad Count: 2676 

ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2004 March 15;10(6):910-912

Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy

Guan-Guan Su, Kong-Han Pan, Nian-Feng Zhao, Su-Hua Fang, Dan-Hong Yang, Yong Zhou


Guan-Guan Su, Kong-Han Pan, Su-Hua Fang, Dan-Hong Yang, Yong Zhou, Department of Infection, Sir Run Run Shaw Hospital affiliated to Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
Nian-Feng Zhao, First Hospital affiliated to Zhejiang University, Hangzhou, 310007, Zhejiang Province, China
Correspondence to: Dr. Guan-Guan Su, Department of Infection, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, Hangzhou, 310016, Zhejiang Province, China. pankonghan@medmail.com.cn
Telephone: +86-571-86090073-6013    Fax: +86-571-86032877
Received: 2003-08-02    Accepted: 2003-09-24

Abstract
AIM: To evaluate the efficacy and safety of lamivudine  treatment of chronic hepatitis B disease in pregnancy.

METHODS: The study group was comprised of 38 chronic HBV patients who were diagnosed pregnant during lamivudine treatment and voluntary to continue the same therapy. The control group was from documented patient data in the literatures. We compared the following parameters with those of a control group: anti-HBV efficacy, complications of pregnancy (abortion, preterm birth, neonatal asphyxia, fetal death, and congenital anomaly), incidence of HBV-positive babies and developmental anomalies in pregnant women treated with lamivudine.

RESULTS: The blocking rate of lamivudine treatment was significantly higher than that of active vaccine immunization for babies with double-positive (HBsAg/HBeAg) mothers with 30-30-10 μg doses of vaccine (74.07%) and with 30-20-10 μg (64.87%). The natural vertical HBV transmission from mother to infant of "double-positive" mothers was 100% (10/10). No pregnancy complication was noted during the observation period, but in the control group the incidences of pregnancy complication were 16.67% (abortion), 43.02%(preterm), 15.62% (neonatal asphyxia), and 4.49% (fetal death), 10.0% (congenital anomaly). No HBV-positive newborn was detected and no developmental anomaly was found in the study group.

CONCLUSION: Lamivudine is helpful to prevent maternal-infant HBV transmission and may reduce the complications of HBV-infected pregnant patients.

Su GG, Pan KH, Zhao NF, Fang SH, Yang DH, Zhou Y. Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy. World J Gastroenterol  2004; 10(6): 910-912
http://www.wjgnet.com/1007-9327/10/910.asp

INTRODUCTION
Throughout the world, over 300 million people have chronic hepatitis B virus (HBV) infection, and more than 75 percent of those affected are of Asian origin[1]. Chronic HBV infection causes cirrhosis, liver cancer, and death[2,3]. The disease is endemic in Africa and Asia, where the virus is transmitted from mother to newborn or between close contacts in early childhood[4-6].
      Chronically infected persons with viral replication are at the highest risk for progressive liver disease[7]. In China, chronic HBV infection is a common clinical occurrence in pregnancy as well as a potentially serious condition[8]. In pregnant patients the complications of HBV occurr more frequently and with a higher mortality[9]. Also vertical transmission of HBV to the infant is common[4,5]. Perinatal transmission of HBV is the most important cause of chronic HBV infection and remains one serious problem despite passive immunization (hepatitis B immune globulin at birth) and active immunization (hepatitis B vaccination according to the standard 3-dose schedule). In different studies high maternal HBV DNA levels were associated with a vaccination breakthrough[10,11]. Recently nucleoside analogues have been used to prevent mother-to-infant transmission of HIV-1[12]. In that setting, lamivudine given during the last weeks of pregnancy in HIV-1 and HBV positive women appeared to be safe[12-15]. Following a similar rationale, there was a clinical trial about the use of lamivudine, a potent inhibitor of HBV replication, in pregnant women with high HBV viral loads in highly endemic countries[16].
     However, few data are available regarding the efficacy and safety of lamivudine treatment for chronic HBV from the early phase of pregnancy. Pharmaceutical inserts regarding lamivudine indicate it is of "uncertain safety" during pregnancy. In this retrospective analysis, we evaluated 38 cases of chronic HBV pregnant patients treated with lamivudine from the early phase of pregnancy for pregnancy-related complications and congentital anomalies.

MATERIALS AND METHODS
Patients
Forty-two chronic HBV-infected women were found to be pregnant during lamivudine treatment and presented to the physician between 2-3 mo of gestation. Then they were enrolled in the study. During the study, one patient chose to terminate her pregnancy, two stopped lamivudine therapy, and one was lost to follow-up. Thus the final study consisted of 38 pregnant patients who continued lamivudine therapy. The pretreatment diagnosis of HBV was based on National Prevention and Treatment Profiles of Viral Hepatitis (2000)[17] criteria with the following criteria: detectable HBsAg and HBeAg/HBeAb in serum, detectable serum HBV DNA, and elevated alanine aminotransferase (ALT) levels (more than 3-4 times normal level). Patients were excluded if they had hepatitis C or D infection. Patients had not received any other antiviral drugs in the preceding 6 mo. All patients were warned about that studies in rabbits had demonstrated lamivudine to result in fetal demise. However, it was also explained that the dosages used in animal studies were nearly 60 times higher than those used in humans (private communication).
    Currently there is a clinical trial in Asia evaluating lamivudine use perinatally in mothers with high HBV viral loads with the goal to reduce vertical HBV transmission to the infants[13]. The patients who earlier stopped lamivudine often experienced significant clinical deterioration. Thus overall we felt it appropriate to consider continuing lamivudine therapy. HBV infection in pregnant women was more serious than in non-pregnant women[9]. All the above were informed to any pregnant patients with HBV infection. Decision was made by patient herself on whether to terminate lamivudine treatment or not.
     The data of complications of HBV hepatitis and HBV-positive babies were based on Prevention and Treatment of Viral Hepatitis study edited by Gao[19]. Lamivudine safety profile was obtained from international studies[13-15,18].

Regimen and parameters
Pregnant women with chronic HBV infection were treated with lamivudine. The dosage, course, efficacy evaluation, follow-up, measures to deal with resistant mutation were based on the Guideline for Lamivudine Clinical Use (2000)[20] and Expert Consensus on Lamivudine Clinical Use (2001)[21]. Complications of pregnancy included abortion, preterm birth, neonatal asphyxia, fetal death, and congenital anomaly[19]. Regular ultrasonic examination was carried out to monitor the safety of the fetus. All newborns were given the standard passive-active immunization or actively immunized at birth. Twelve babies were tested of HVB DNA (PCR), HBsAg, HBeAg, anti-HBs, anti-HBe, anti-HBc at birth before HBIg administration (T0) and at the 6th mo (T6) and the 12th mo (T12) after birth. The percentage of HBV-positive babies was calculated. The health status and development of babies were assessed by the local children healthcare institution. All children were followed-up and documented.

RESULTS
Antiviral efficacy
HBV-DNA was converted to negative in 35 patients (92.11%) of the study group. HBeAg was converted to negative in 12 patients (31.58%). The rate of HBeAg seroconversion (loss of HBeAg or development of antibody to HBeAg) was 26.32% (10/38). The normalization rate of ALT was 73.68% (28/38). The rate of resistant mutation was 11.43% (4/35). Lamivudine efficacy was similar to other reports in the international medical literatures[13-15]. ALT normalization may have been confounded by hepatic injury of pregnancy. Thus the complete efficacy of lamivudine was difficult to assess.

Incidence of HBV-positive baby (Table 1)
Twelve maternal-baby pairs were evaluated for HBV markers (HBsAg, HBeAg, anti-HBs, and anti-HBe,anti-HBc) before and after delivery. All 12 mothers were double positive (HBsAg/HBeAg) before lamivudine treatment. Although the HBV-DNA parameters of all 12 mothers were converted to negative prepartum, 8 mothers remained HBeAg-positive, 1 HBeAg negative, and 3 reached seroconversion. Of the 8 mothers who were HBeAg-positive at childbirth, 3 babies were HBsAg-positive at birth (T0), but turned negative at T6 and T12 postpartum. The other babies were all HBsAg- negative during 12 months of follow-up. Thus after one year, 100% of the babies were HBsAg-negative. But in control group, the blocking rates of active vaccine immunization for babies with double-positive (HBsAg/HBeAg) mothers were 74.07% with 30-30-10 μg doses of vaccine and 64.87% with 30-20-10 μg. The natural vertical HBV transmission from mother (double-positive) to infant was 100% (10/10)[19]. The prevention of HBV maternal-infant transmission was very significant in lamivudine-treated mothers.

Table 1  Blocking of maternal transmission in HBsAg and HBeAg double-positive mothers[19]  

  n HBsAg(+) HBV-DNA(+) Blocking rate
  T0 T6 T12    
Lamivudine treatment  12 3 0 0 0 100.00
Vaccine 30-30-10 mg 81   21 21 21 74.07
Vaccine 30-20-10 mg 37   13 13 13 64.87
Natural transmission 10   10 10 10 0.00

Complications of pregnancy (Table 2)
The infants of lamivudine-treated mothers were delivered at full term without any complication. The incidence of pregnancy complication was lower in the study group than in the control group of pregnant mothers with chronic HBV[19].

Table 2  Complications of pregnancy in different groups [19]  

Abortion(%) Preterm(%) Neonatal asphyxia (%) Fetal death (%) Congenital anomaly (%)
Lamivudin 0/38 0/38 0/38 0/38 0/38
Control 16.67 43.02 15.62 4.49 10
(1/6) (37/86) (14/89) (4/89) (1/10)

Control of viral hepatitis activity (Table 3)
Although three out of 38 patients in the study group did not convert to HBV-DNA-negative within one year, ALT normalized in all three patients. Ten patients in the study group converted to HBV-DNA-negative, but their ALT remained abnormal. They were included in the pregnancy liver injury group. Six patients were HBeAg-negative, and four patients had seroconversion for HBeAb. A resistant HBV mutant emerged in four cases though their ALT remained normal. Thus overall hepatitis activity was controlled in all the study patients (100%). In the two patients who quitted lamivudine after the consultation, active hepatitis recurred within 6 months. Honkoop et al reported that the incidence of "lamivudine withdrawal hepatitis" was 17% (7/41)[22]. Hepatitis activity was better controlled in lamivudine treatment group than in the group who quitted lamivudine therapy (Table 3).

Table 3  Control of hepatitis activity[22]  

  n Active hepatitis (%)
Lamivudine treatment during pregnancy 38 0 (0.00)
Stop lamivudine while pregnant 2 2 (100.00)
Stop lamivudine 41 7 (17.07)

Infant development and health
Community maternal-child health clinics failed to detect any unfavorable outcome related to the infaint's health and development.

DISCUSSION
It has been well-known that the pregnant women chronically infected with HBV have more complications and a higher mortality during pregnancy[5,8,9]. Lamivudine has been found to be an effective treatment strategy for chronic HBV[15]. However, its use is not recommended during pregnancy especially during the first trimester because animal studies have demonstrated lethal effects on the rabbit fetus (private communication). In our study 38 pregnant women with chronic HBV infection continued lamivudine therapy during the entire pregnancy. Their decision to continue its therapy was voluntary after informed consent. They were all provided with information about the drug benefits and risks. Our results indicated lamivudine therapy not only provided a protective effect against maternal-infant HBV transmission, but decreased the likelihood of active HBV infection in the mother. Further complications were minimal compared with the control group. These results should be presented to a mother contemplating continuation of lamivudine therapy during pregnancy.
      Pregnancy complications are likely caused by the activity of hepatitis B virus in mothers with chronic HBV infections. The rate of vertical maternal-infant HBV transmission was 90-100% in mothers who were double positive for both HBsAg and HBeAg[19]. It is probable that such a high transmisson rate has been led by the high viral load[10,11]. The data in our study indicated lamivudine was able to neutralize hepatitis activity and reduction in the viral load might result in fewer pregnancy complications and prevent maternal-infant HBV transmission. This benefit may well outweigh the risk of lamivudine's early toxic effects on the infant during the first trimester. Lamivudine has been found belonging to the L-form enantiomorph nucleotide analogue which is negatively selective for the human nucleotide[15]. Toxicity was detected only at very high dosages of 1 000 times higher than the recommended human dosages. The dosage used in animals was 60 times greater than that used in human (private communication). Thus currently recommended lamivudine dosages for human may represent little risk to the pregnant mother.
     However, there are several concerns about our current study. First, our study was not designed as a randomized- placebo-controlled study, thus any improvement in the study group could be due to such confounding factors as "self-selection" bias, or observer bias. Second, the study group was small and thus might lack power to distinguish a true difference between the treated group and the control group. However, we do consider the study to be of value in raising the question of benefit of lamivudine treatment of chronic HBV in pregnancy. Further studies, especially larger well-designed placebo-controlled studies are needed to confirm a true beneficial effect of lamivudine therapy for chronic HBV infection in pregnancy.

REFERENCES
1    Maynard JE. Hepatitis B: global importance and need for control. Vaccine 1990; 8: S18-20
2    Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective
      study. Hepatology 1988; 8: 493-496
3    Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY, Chen DS. Universal hepatitis B vaccination 
      in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl 
      J Med 1997; 336: 1855-1859
4    Stevens CE, Neurath RA, Beasley RP, Szmuness W. HBeAg and anti-HBe detection by radioimmunoassay: correlation 
      with vertical transmission of hepatitis B virus in Taiwan. J Med Virol 1979; 3: 237-241
5    Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, Chen RJ, Margolis HS, Huang CH, Maynard JE. Prevention of
      perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind
      placebo-controlled and comparative trial. Pediatrics 1985; 76: 13-18
6    Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigen-carrier mothers. J Infect Dis 
      1983; 147: 185-190
7    de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in
      hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992; 103: 1630-1635
8    Yang H, Chen R, Li Z, Zhou G, Zhao Y, Cui D, Li S, Han C, Yang L. Analysis of fetal distress in pregnancy with hepatitis B
      virus infection. Zhonghua Fuchanke Zazhi 2002; 37: 211-213
9    Khuroo MS, Kamili S. Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy. J Viral Hepat
      2003; 10: 61-69
10  Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention of hepatitis B virus carrier state in infants according to
      maternal serum levels of HBV DNA. Lancet 1989; 1: 406-410
11  del Canho R , Grosheide PM, Mazel JA, Heijtink RA, Hop WC, Gerards LJ, de Gast GC, Fetter WP, Zwijneberg J, Schalm
      SW. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982-1992: Protective efficacy and long-
      term immunogenicity. Vaccine 1997; 15: 1624-1630
12  Faucher P, Batallan A, Bastian H, Matheron S, Morau G, Madelenat P, Benifla JL. Management of pregnant women 
      infected with HIV at Bichat Hospital between 1990 and 1998: analysis of 202 pregnancies. Gynecol Obstet Fertil 
      2001; 29: 211-225
13  van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during
      pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat 2003; 10: 294-297
14  Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, van Leeuwen R, Goodwin C, Harrigan PR, Moore KH, Stone C, 
      Plumb R, Johnson MA. Pharmacokinetics and antiretroviral activity of  lamivudine alone or when coadministered 
      with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect 
      Dis 1998; 178: 1327-1333
15  Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet 
      1999; 36: 41-66
16  Van Nunen AB, de Man RA, Heijtink RA, Niesters HG, Schalm SW. Lamivudine in the last 4 weeks of pregnancy to 
      prevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol 2000; 32: 1040-1041
17  Branch society of Infectious Disease and Parasitology and Branch society of Hepatology of Chinese Medical Association.
      National Preventiont and Treatment Profiles of Viral Hepatitis (2000). Zhonghua Chuanranbing Zazhi 2001; 19: 56-62
18  Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF. A
      one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 
      1998; 339: 61-68
19  Gao SZ. Research on prevention and treatment of viral hepatitis. Beijing: Beijing pub 1993: 38-46, 286-291
20  Expert team for lamivudine clinical use. The year 2000 guideline for lamivudine clinical use. Zhonghua Ganzangbing 
      Zazhi 2000;8: 249-250
21  Expert team for lamivudine clinical use. Expert consensus on lamivudine clinical use (2001). Zhonghua Ganzangbing 
      Zazhi 2002;10: 157-158
22  Honkoop P, de Man RA, Niesters HG, Zondervan PE, Schalm SW. Acute exacerbation of chronic hepatitis B virus 
      infection after withdrawal of lamivudine therapy. Hepatology 2000; 32: 635-639

   Edited bGupta MK and Wang XL  Proofread by Xu FM   

 

Reviews Add
more>>


Related Articles:
Lamivudine does not increase the efficacy of interferon in the treatment of mutant type chronic viral heaptitis B
Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B
Coinfection of TT virus and response to interferon therapy in patients with chronic hepatitis B or C
Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance
Portalsystemic hemodynamic changes in chronic severe hepatitis B: An ultrasonographic study
more>>