Hepatitis B Exacerbation with a Precore Mutant Virus Following Withdrawal of Lamivudine in a Human Immunodeficiency Virus-infected Patient

Case Reports

192

doi:10.1053/jinf.2000.0724, available online at http://www.idealibrary.com on

Hepatitis B Exacerbation with a Precore Mutant Virus Following Withdrawal of Lamivudine in a Human Immunodeficiency Virus-infected Patient D. Neau*1, E. Schvoerer2, D. Robert1 , F. Dubois3, H. Dutronc1, H. J. A. Fleury2 and J. M. Ragnaud1 1

Fédération des Maladies Infectieuses, 2 Laboratoire de Virologie, Hôpital Pellegrin, Bordeaux, 3 Laboratoire de Virologie, Centre Hospitalo-Universitaire, Tours, France

Chronic active hepatitis B exacerbations have been reported following development of resistance to or withdrawal of lamivudine in HIV-infected patients. A 38-year-old woman with HIV and chronic HBV infections was hospitalized because of acute hepatitis. The occurrence of cytolysis with replication of HBV 2 months after withdrawing lamivudine suggests that our patient experienced a severe reactivation of HBV infection due to the modification of her treatment. Sequencing of the HBV precore region showed the strain to be a mutant. We conclude that lamivudine should not be stopped in HIV- and HBV-infected patients, but could be continued at the dose of 100 mg/day as used in isolated HBV infection. © 2000 The British Infection Society

Introduction Lamivudine is an oral nucleoside analogue widely used in the treatment of human immunodeficiency virus (HIV) infection. It has also been shown to inhibit the RNA- and DNA-dependent DNA polymerase activity of hepatitis B virus (HBV).1 Chronic active hepatitis B exacerbations have recently been reported following development of resistance to, or withdrawal of, lamivudine in HIV-infected patients.1 We describe a case of severe hepatitis B exacerbation involving an hepatitis B precore mutant virus following withdrawal of lamivudine.

Case Report A 38-year-old woman was referred to our hospital in October 1998 because of jaundice. She was first diagnosed with HIV and chronic HBV infections in 1994. Serological testing was positive for B surface antigen (HBsAg) and antibodies to B core (antiHBc), negative for hepatitis B e antigen (HBeAg) and positive for antibodies to HBeAg. From January 1994 to August 1998, regular liver function tests were normal except on three occasions when there were moderately increased ALT levels (less than twice the upper limit of normal). In October 1997, in response to an increase in the plasma HIV-1 RNA level (9000 copies/ml), antiretroviral treatment with zidovudine and zalcitabine was modified and a regimen of stavudine and lamivudine was started (Table I). In July 1998, lamivudine was discontinued because of a new rise in HIV-1 RNA * Please address all correspondence to: D. Neau, Service du Professeur Ragnaud, Hôpital Pellegrin, Place Amélie Raba-Léon, 33076 Bordeaux Cedex, France. Accepted for publication 17 July 2000. © 2000 The British Infection Society

(18 600 copies/ml). The CD4
T-lymphocyte count was 567/mm3. Didanosine and nevirapine were associated with stavudine. The patient was hospitalized with manifestations including malaise, anorexia, weight loss, jaundice, and abdominal pain. Clinical examination revealed a tender hepatomegaly. Liver function studies showed evidence of cytolysis and increased serum bilirubin (Table I). The coagulation status was altered (prothrombin time: 43%; factor V: 51%). Diagnostic work-up was negative for hepatitis A, C, and E. No hepatitis delta virus (HDV) antigen was found. Evidence for anti-delta antibodies of the IgM class was equivocal (optical density at the limit of significance), but the total antidelta antibodies were negative. Serology for hepatitis B showed no modification apart from anti-HBc of the IgM class at the threshold of positivity. Serum HBV DNA level, determined using a branched-DNA hybridization test (Quantiplex HBV DNA assayChiron), was strongly positive (2962 Meq/ml). In samples taken 2 months before and 2 months after the hepatitis flare, no evidence of delta virus infection was found (HDV antigen, IgM antiHDV, total anti-HDV), suggesting a mild artifactual reaction of the IgM anti-HDV and eliminating the hypothesis of HDV infection. Furthermore, sequencing of the HBV precore region was performed with the classical Sanger method using DRhodaminelabelled dideoxynucleotides (Perkin Elmer, France). Sequence reactions were conducted on GeneAmp PCR system 9600 thermocycler (Perkin Elmer) and sequences read on the automated sequencer ABI prism 377 (Applied Biosystems Perkin Elmer). Thus, the strain was shown to be a mutant with a stop codon (instead of a tryptophan in position 28), explaining the absence of HBeAg, and consistent with a weak IgM anti-HBc reactivity. The clinical status of the patient improved within a few days, with resolution of systemic symptoms. The blood tests spontaneously returned to normal within a matter of weeks.

– –

AZT DDC

100

–

AZT DDC –

–

–

–

N

N

–

AZT DDC

–

–

–

N

N

–

AZT DDC

–

–

–

N

N

D4T 3TC 3.1

:0.7

–

–

–

43

N

AZT DDC

–

–

–

65

N

D4T DDI nevirapine :0.7

–

–

–

N

N

27/7/98

–

–

43 (51) 1.96

43 (23)

5605

2326

2962

–

35 (52) 1.75

124 (87)

5184

3150

–

–

41 (55) 1.52

195 (141)

4802

2378

–

–

54 (95) 1.70

219 (153)

2025

855

8.5

–

2.62

95

119 (71)

836

183

–

–

–

–

69 (43)

530

99

–

–

4

30

13

5/1/99

AZT AZT 3TC 3TC nevirapine nevirapine – 1.5

–

–

–

72

41

3/10/98 5/10/98 7/10/98 9/10/98 12/10/98 15/10/98 30/10/98

N, normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time.

HBV DNA (Meq/ml)

N

N

2/4/96 8/7/96 29/10/96 25/2/97 14/5/97 3/10/97

Antiretroviral treatment and laboratory findings.

AST (IU/l) N:35 ALT (IU/l) N:40 Total bilirubin (µmol/l) (direct bilirubin) PT(%) (factor V) Fibrinogen (g/l) Antiretroviral treatment

Table I.

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Case Reports

Discussion As in two patients of Bessesen et al.1, and given the clinical and biological evidence eliminating an infection by another hepatotropic virus, the occurrence of cytolysis with replication of HBV 2 months after withdrawing lamivudine suggests that our patient experienced a severe reactivation of HBV infection due to the modification of her treatment. Nevirapine could have been incriminated as an additional cause of hepatitis, but the drug was reintroduced after the acute episode without any biological consequence. In patients who had previously untreated chronic hepatitis B but not HIV infection, treatment with lamivudine for 1 year was shown by Dienstag et al. to decrease histological liver abnormalities and to increase the rate of HBeAg seroconversion, which they defined as the loss of HBeAg in serum, undetectable serum HBV DNA levels, and the presence of antibodies against HBeAg.2 A post-treatment elevation of ALT (more than three times baseline) has been reported within 8–24 weeks (median, 12 weeks) following withdrawal of lamivudine in 16% of HIVnegative subjects treated for 3–6 months.3 In a recent study concerning patients treated for 52 weeks, 22% of the patients had grade III cytolysis (defined as ALT concentration 3–10 times the baseline value) within 16 weeks after discontinuation of lamivudine (6% in the placebo group). In the same report, 3% of the patients had grade IV cytolysis within the same period of time (defined as ALT greater than 10 times the baseline value) as opposed to 2% in the placebo group.2 However, more severe liver involvement appears to be rare.2,3 Honkoop et al. reported the case of a 29-year-old man who experienced hepatitis B reactivation 4 months after discontinuing lamivudine, an increase in aminotransferases 100 times the upper limit of normal, jaundice and a fall in clotting factors below 50%.3 In our patient, the hepatitis B reactivation with high levels of HBV DNA occurred approximately 2 months after discontinuation of lamivudine. Patients in other series who received lamivudine for 3–6 months also exhibited return of serum HBV DNA

levels to baseline within 2 months after discontinuation of lamivudine. However, patients treated for 52 weeks experienced a slower re-increase toward serum HBV DNA baseline levels (the median levels were approximately 55% below the baseline levels at week 68).2 Infection with precore mutant virus is associated with more severe liver disease and a higher incidence of fulminant hepatitis,4 a poor response to interferon therapy, and severe recurrent disease after liver transplantation.5 The reactivation in our patient was linked to such a mutant strain. Our observation underlines, therefore, that the presence of anti-HBe antibodies does not exclude the possibility of such a reactivation. In conclusion, withdrawal of lamivudine in patients co-infected with HBV and HIV should be followed by liver function monitoring for several weeks, even in anti-HBe positive carriers. Our case suggests that such surveillance is crucial because of the potential severity of hepatitis B exacerbation. Moreover, when antiretroviral therapy has to be modified, lamivudine should not be stopped, but should be continued at the dose of 100 mg/day as used in isolated HBV infection.

References 1 Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virusinfected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis 1999; 28: 1032–1035. 2 Dienstag JL, Schiff ER, Wright TL et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999; 341: 1256–1263. 3 Honkoop P, de Man RA, Heijtink RA, Schalm SW. Hepatitis B reactivation after lamivudine. Lancet 1995; 346: 1156–1157. 4 Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben Porath E. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991; 324: 1705–1709. 5 Angus PW, Locarnini SA, McCaughan GW, Jones RM, McMillian JS, Bowden DS. Hepatitis B virus precore mutant infection is associated with severe recurrent disease after liver transplantation. Hepatology 1995; 21: 14–18.