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Molecular analysis of hepatitis B virus (HBV) in an HIV co-infected patient with reactivation of occult HBV infection following discontinuation of lamivudine-including antiretroviral therapy

  • Andrea Costantini1,
  • Katia Marinelli2,
  • Giulia Biagioni2,
  • Alessia Monachetti2,
  • Monica L Ferreri2,
  • Luca Butini1,
  • Maria Montroni1,
  • Aldo Manzin3 and
  • Patrizia Bagnarelli2Email author
Contributed equally
BMC Infectious Diseases201111:310

DOI: 10.1186/1471-2334-11-310

Received: 12 July 2011

Accepted: 4 November 2011

Published: 4 November 2011

Abstract

Background

Occult hepatitis B virus (HBV) infection (OBI) is characterized by HBV DNA persistence even though the pattern of serological markers indicates an otherwise resolved HBV infection. Although OBI is usually clinically silent, immunocompromised patients may experience reactivation of the liver disease.

Case presentation

We report the case of an individual with human immunodeficiency virus (HIV) infection and anti-HBV core antibody positivity, who experienced severe HBV reactivation after discontinuation of lamivudine-including antiretroviral therapy (ART). HBV sequencing analysis showed a hepatitis B surface antigen escape mutant whose presence in an earlier sample excluded reinfection. Molecular sequencing showed some differences between two isolates collected at a 9-year interval, indicating HBV evolution. Resumption of ART containing an emtricitabine/tenofovir combination allowed control of plasma HBV DNA, which fell to undetectable levels.

Conclusion

This case stresses the ability of HBV to evolve continuously, even during occult infection, and the effectiveness of ART in controlling OBI reactivation in HIV-infected individuals.

Background

Occult hepatitis B virus (HBV) infection (OBI) is, by definition, characterized by infectious HBV DNA in liver, blood, or both, in the absence of hepatitis B surface antigens (HBsAg) [1]. Isolated anti-HBV core antibodies (anti-HBc) have been shown to be a predictive marker of OBI [2]. Isolated anti-HBc [3, 4] and OBI are often seen in patients with human immunodeficiency virus (HIV) infection [5, 6], where they are more prevalent than in non-coinfected individuals [7]. Reactivation of chronic HBV in presence of HBsAg has been reported in immunosuppressed subjects and in those with HIV infection following discontinuation of antiretroviral therapy (ART) [8, 9].

There are few reports addressing OBI reactivation during HIV infection [10, 11] and fewer still providing an extensive description of the molecular characteristics of occult HBV reactivation [12]. Nucleot(s)ide analogues (NA) lamivudine, emticitabine and tenofovir are known to be effective against both HIV and HBV, providing a unique opportunity to treat coinfected patients [13, 14], but little information is available to establish whether resumption of ART for HIV/HBV coinfection may restore control of HBV replication after OBI reactivation.

Case presentation

A 46-year-old woman with a 25-year history of HIV disease, who experienced two episodes of occult HBV reactivation after interrupting a lamivudine-containing ART regimen. At the time of the diagnosis of HIV infection (October 1985) she also tested negative for HBsAg and positive for anti-HBsAg and anti-HBc (table 1). Lamivudine-containing ART was started in November 1996 and repeatedly changed until August 2000, for a variety of reasons (table 2). In addition, the patient did not fully adhere to therapy, and complete suppression of HIV viremia was never obtained (not shown). In September 2000 she discontinued the ART treatment; in few months HIV RNA levels rose to more than 470,000 copies/ml and CD4+ T cell counts dropped to 9/mmc (table 2), leading to two episodes of esophageal candidiasis, interstitial pneumonia due to Chlamydia pneumoniae, and disseminated Mycobacterium avium infection (not shown). ART including lamivudine and tenofovir, was resumed in April 2002 and continued until September 2009. Improved adherence to treatment resulted in undetectable plasma HIV-RNA and high-level immune reconstitution (tables 1 and 2).
Table 1

Sequential serological, biochemical and virological findings in an HIV-infected individual with markers of prior HBV infection at baseline.

Characteristics

Date (month/year)

 

10/85

11/87

10/001

01/011

05/011

11/061

01/071

01/081

05/09

12/09

02/10

02/10

03/10

04/10

05/10

07/10

HBsAg (IU/ml)

NEG

NEG

0.00

0.00

0.00

0.00

0.00

0.00

0.00

--

168

183

132

66

0.1

0.0

Anti-HBs (mIU/ml)

POS

POS

<10

<10

<10

<10

<10

<10

<10

--

140

124

87

61

50

24

Anti-HBc

POS

POS

POS

POS

POS

POS

POS

POS

POS

--

POS

POS

POS

--

POS

POS

Anti-HBc IgM

NEG

NEG

--

--

--

--

--

--

--

--

POS

POS

POS

NEG

--

--

HBeAg

NEG

NEG

--

--

--

--

--

--

--

--

POS

NEG

NEG

--

--

--

Anti-HBe

NEG

NEG

--

--

--

--

--

--

--

--

POS

POS

POS

--

--

--

HBV DNA (IU/ml)

--

--

R (3)

R (7)

19

NR

NR

NR

NR

--

88,185

5,622

998

26

R (4)

NR

AST (U/l)

17

19

31

58

30

20

21

23

28

80

2,702

143

41

--

23

19

ALT (U/l)

14

16

35

68

37

14

14

14

19

111

2,577

306

42

--

17

21

CD4+ T (cells/µl)

891

883

48

29

48

478

580

516

513

304

291

--

--

--

423

333

HIV-RNA 2 (copies/ml)

--

--

147,018

222,107

146,707

<50

<50

NR

NR

80,558

--

--

734

--

NR

NR

Antiretroviral therapy

Naive

Naive

No3

No3

No3

Yes4

Yes4

Yes4

Yes4

No5

No5

Yes6

Yes6

Yes6

Yes6

Yes6

IU/ml = International Units/milliliter; mIU/ml = International milliunits/ml; U/l = Units/liter; NEG = negative; POS = positive; R = reactive below cut-off (<10IU/ml); HBV DNA calculated by the regression curve in brackets; NR = not reactive; -- = not determined.

1molecular and serological markers of HBV infection were retrospectively determined in February 2010 using automated Abbott HBV RealTime and Abbott ARCHITECT HBV assays, respectively

2HIV viremia was evaluated by Versant HIV RNA assay 3.0 (bDNA; Siemens Healthcare Diagnostics, Deerfield, IL) up to 01/2007 and by Abbott HIV RealTime since 01/2008.

3Previous antiretroviral therapy (Didanosine, Lamivudine, Nevirapine) was started on 04/2000 and interrupted on 08/2000; Lamivudine daily dose was 300 mg.

4Therapy was resumed in 02/2002 with different drug combinations including Lamivudine (300 mg daily) with or without Tenofovir (245 mg daily).

5Therapy (Lamivudine and Atazanavir) was interrupted on 10/2009.

6Therapy was resumed in 02/2010, including co-formulated Emtricitabine/Tenofovir (200/245 mg daily) plus boosted Darunavir.

Table 2

Changes in ART during follow-up and reasons for each change.

ART combination

Start

Stop

Reasons for the changes

Lowest number of CD4+ T cells/mmc

Highest HIV-RNA load (copies/ml)

Zidovudine, Lamivudine

11/1996

07/1997

Upgrade

147

--

Zidovudine, Lamivudine, Saquinavir

08/1997

02/2000

Poor adherence, virological failure

50

90,387

Stavudine, Lamivudine, Efavirenz

03/2000

04/2000

Skin rash

95

1,164

Stavudine, Lamivudine, Nevirapine

05/2000

08/2000

Patient decision

65

1,245

INTERRUPTION

09/2000

01/2002

--

9

472,578

Stavudine, Lamivudine

02/2002

04/2002

Upgrade

--

--

Stavudine, Lamivudine, Lopinavir/r*

05/2002

04/2003

Patient decision, diarrhea

74

<50

Tenofovir, Lamivudine, Indinavir/r*

05/2003

01/2009

Patient decision

245

<50

Didanosine, Lamivudine, Atazanavir

02/2009

04/2009

Simplification

516

<40

Lamivudine, Atazanavir

05/2009

09/2009

Patient decision

531

119

INTERRUPTION

10/2009

02/2010

--

291

80,558

Emtricitabine/Tenofovir, Darunavir/r*

02/2010

--

--

333

734

*r = boosted ritonavir.

Of note, since 1985 AST and ALT values were consistently in the normal range except on two occasions (May 1999, not shown, and January 2001, table 1), when slight increases were noted but not further investigated.

Another interruption of ART in October 2009 resulted in a sharp rise in aminotransferase levels to over 2,500 U/l in February 2010 (table 1), while CD4+ T cell counts fell from 531 to 291/mmc and HIV-RNA rose to >80,000 copies/ml. Antibodies against hepatitis C and hepatitis D virus were negative, but detection of serological markers of overt HBV infection (table 1) led to a diagnosis of OBI reactivation, which was further investigated at the molecular level.

A portion of the polymerase gene was sequenced using the PCR product obtained with primers P1 (forward outer = 5'-TCTAGACTCGTGGTGGACTTCTC) and P4 (reverse outer = 5'-TACAGAGAAAGGCCTTGTAAGTTG) which amplified an 880 bp fragment of HBV DNA from nucleotide 249 to 1128 (numbered according to an EcoRI site). This allowed analysis of mutations in the overlapping surface (s) and reverse transcriptase (rt) genes of HBV. As shown in table 3 and Figure 1, the patient harboured a genotype D (subtype D1) HBV strain and no NA resistance-associated mutations were selected in the polymerase gene. Interestingly, envelope escape variants were detected due to G145R, D144DE and P142LP mutations. The presence of HBsAg escape variants and the availability of seven frozen samples collected between October 2000 and May 2009 prompted a retrospective analysis for the molecular and serological markers of viral activity. Three of the seven samples collected during the aminotransferase "blips" between October 2000 and May 2001 exhibited very low-level viremia (table 1) using highly sensitive HBV RealTime (Abbott Laboratories. Abbott Park, IL; limit of quantification 10 international units per millilitre [IU/mL]), and serological analysis revealed isolated anti-HBc. Attempts to obtain an overlapping polymerase and surface antigen sequence was successful with the May 2001 specimen, using a 5× concentration and nested PCR with inner primers P2 (forward inner = 5'-TCCTGTCCTCCAACTTGTCCTG) and P3 (reverse inner = 5'-TGTGGCAATGTACCCCAACTTCCA) that amplified a 571 bp fragment internal to the P1-P4 product, from nucleotide 346 to 916. This sequence showed the G145R and P142L, but not the D144DE HBsAg escape variant. The sample also contained the V224AV quasispecies, which was subsequently undetectable (table 3 and Figure 1). Although we cannot exclude that the different quasispecies were present in 2010, our date indicate that during the course of treatment, the species with D144E probably became more dominant and the species with V224A decreased in proportion. Altogether these data can be regarded as signs of HBV evolution: however, we acknowledge that lacking of cloning analysis of HBV quasispecies is a possible limitation to these conclusions.
Table 3

Genetic variability of hepatitis B virus during occult infection.

Sequence information

Sample ID (HBV viral load)

SL05/2001 (19 IU/ml)

Genotype (subtype)

D (D1 - 97.95% 1 )

rt-HBV mutations: aa 79-255 3

N118H, Y135S, R153Q, N248H 2

s-HBV mutations: aa 71-227 stop 3

R122K, P142LP, G145R, F179FS, V224AV 2

Escape mutations

142L, 145R

Resistance prediction

None4

Sample ID (HBV viral load)

SL02/2010 (88,185 IU/ml)

Genotype (subtype)

D (D1 - 98.23% 1 )

rt-HBV mutations: aa 43-330 3

N118H, Y135S, R153KQ, N248H 2

s-HBV mutations: aa 35-227 stop 3

R122K, P142LP, D144DE, G145R, F179FS 2

Escape mutations

142L, 144E, 145R

Resistance prediction

None4

1 percent identity to the subtype as reported by HIV-GRADE_HBV-tool analysis (software available at http://www.hiv-grade.de/hbv_grade/deployed/grade.pl?program=hbvalg).

2 mutated residues are defined with respect to the HBV genotype D consensus sequence, residues in bold indicate changes involving both rt and s genes.

3 aa = amino acid; the range of sequenced amino acid residues covers the whole region of rt-HBV involved by antiviral resistance and the "a" determinant neutralizing antibody-binding domains of the s-HBV gene; aa numbered according to Stuyver et al [26].

4 the resistance prediction and reference sequence were assessed by HIV-GRADE_HBV-tool coupled with the interpretative algorithm Geno2Pheno [hbv] (available at http://hbv.bioinf.mpi-inf.mpg.de/index.php).

https://static-content.springer.com/image/art%3A10.1186%2F1471-2334-11-310/MediaObjects/12879_2011_Article_1657_Fig1_HTML.jpg
Figure 1

Alignment of HBV genes. Alignment of the amino acid (aa) sequences of the HBV polymerase (A) and surface (B) genes amplified from samples collected during two episodes of OBI reactivation. The genotype D consensus sequence is shown as a reference in the alignment performed by HIV-GRADE_HBV-tool. Dashes indicate identity to the reference, points indicate sequence gaps due to primer design. Substitutions and ambiguities indicating presence of quasispecies in the direct sequence are shown. Differences between the two sequences are in bold. * = stop codon; aa numbered according to Stuyver et al [26]. The two sequences have been submitted to the GenBank and assigned accession no. JF827279 (SL05_2001), JF827280 (SL02_2010).

The patient resumed ART to control HIV replication and counteract HBV reactivation. A regimen including emtricitabine/tenofovir plus boosted darunavir was prescribed in mid February 2010. After three months aminotransferase levels reverted to normal; follow-up of serological HBV markers showed the sequential disappearance of hepatitis B e antigen (HBeAg), IgM class anti-HBc, and HBsAg. Plasma HBV DNA gradually fell to undetectable levels (table 1).

Conclusions

We describe the case of an HIV-infected patient with serological evidence of resolved HBV infection who experienced two distinct episodes of OBI reactivation after interrupting of lamivudine-containing ART regimens. In both cases, reintroduction of ART including HBV-active NA (lamivudine or emtricitabine/tenofovir) was followed by aminotransferase normalization and clearance of plasma HBV DNA. Different results have been reported in two HIV/HBV coinfected patients [10, 12]. The reasons for the different outcomes are unclear, since only few cases of OBI reactivation among HIV-infected individuals have been reported to date. Emergence of HBV drug resistance following OBI reactivation was observed neither in our patient nor in the one described by Bagaglio and co-workers [12]; residual HBV replication before the overt phase of occult HBV reactivation was excluded in both patients. However, residual HBV replication and reactivation without prior HBV DNA positivity have both been described in HIV-infected patients [15, 16].

Interestingly, OBI reactivation in our patient was treated with a drug combination including emtricitabine and tenofovir, while Bagaglio and co-workers used a single-drug tenofovir-based approach, and Chamorro and colleagues a scale up approach where tenofovir was introduced years after lamivudine [10]. Conceivably, different HBV-active regimens may determine different outcomes in OBI reactivation, and combination therapy may have in principle better chances to obtain long-term control of HBV replication than single-drug regimens, especially in the context of HIV-related immune suppression.

One of the most intriguing aspect of HBV pathogenesis is the accumulation, already in the early phase of infection, of covalently closed circular (ccc)DNA in the nuclei of infected hepatocytes, which is the basis for the establishment of viral persistence. cccDNA is the hepatic reservoir for HBV infection, found in all patients studied up to a decade after resolution [17] and in 50% of patients who had acute self-limited HBV infection 30 years previously [18]. Intrahepatic cccDNA can be considered as a candidate for OBI reactivation when immunological host conditions deteriorate.

In our patient molecular analysis of HBV DNA during reactivation disclosed an HBsAg escape variant, as shown by G145R and D144DE mutations in the HBsAg "a" determinant. Since HBV reinfection could not be completely ruled out, we analyzed the serum and plasma samples collected during the previous aminotransferase "blip", and found that the G145R variant was already present at that time.

Due to overlapping envelope and polymerase genes, the s-G145R variant is associated with the rt-R153Q mutation, which results in expression of an altered polymerase that is replication competent but seems to have reduced replication efficiency [1921]. Among the few differences observed between the direct sequences of the 2001 and 2010 specimens, the s-HBV D144E variant seems to be important, since it determines a Q153K back mutation at the rt-HBV level. It is conceivable that rt-153K could be a secondary mutation connected with a fitness gain. Interestingly, coexistence of HBsAg and anti-HBs in 2010 specimens could be explained by presence of heterologous subtype-specific antibodies possibly directed against an HBsAg subtype different from HBsAg expressed in the past (primary) infection. At least five remarkable mutations were detected within the neutralizing epitope cluster of the surface protein in the genotype D consensus sequence, of which the D144E mutation has been described as a variant with "d" determinant opposite to the "y" determinant more frequently detected in genotype D [22]. Although it is impossible to establish whether this variant emerged in the 9-year interval between the two OBI episodes, or during the latest reactivation, our data indicate that HBV evolution may have occurred during OBI, and that this and some other mutations may have led to the induction of less effective antibody response against a reactivated virus.

OBI reactivation is a consequence of deteriorated immune function [23, 24]; in our patient the overt phase of severe HBV reactivation arose in conjunction with decreased CD4+ T cell counts. However, clinical and biochemical levels reflecting severe HBV reactivation were not observed at other times when the patient's immune status was profoundly impaired (see table 2): this was not a surprise, in that a severe reactivation of hepatitis B requires a competent immune systems, and this is what happened during immune reconstitution in the absence of anti-HBV active drugs. Overall, it may be speculated that a qualitative, rather than a quantitative worsening of HBV-specific T cell responses may favour OBI reactivation in HIV-infected patients. Notably, persistence of functional T cell response has been reported in individuals with OBI and in HBsAg-inactive carriers [25].

The clinical significance of occult hepatitis is still a matter of controversy and further studies should examine the long-term clinical implications of occult HBV in HIV-infected patients.

In summary, this case stresses that ART for HIV/HBV coinfection can control OBI reactivation in HIV-infected individuals, and that in patients with previous HBV infection the withdrawal of anti-HIV drugs with activity against HBV must be approached with caution. Moreover, molecular HBV sequencing data support the hypothesis that HBV cccDNA, is not only the genetic archive for resistant viral genome emerging during treatment of chronic HBV, but also the genetic reservoir allowing continuous HBV evolution, through ongoing low-level replication, even during occult infection.

Consent

The study was approved by the institutional ethical committee of the Università Politecnica delle Marche. Written informed consent according to Helsinki protocol was obtained from the patient for publication of this case report.

Notes

Declarations

Authors’ Affiliations

(1)
Clinical Immunology Unit, Department of Clinical and Molecular Sciences, Università Politecnica Marche
(2)
Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche
(3)
Section of Medical Microbiology, Department of Biomedical Science and Technology, Università di Cagliari

References

  1. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky JM, Pollicino T, Prati D, Puoti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR, Zoulim F: Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008, 49: 652-657. 10.1016/j.jhep.2008.07.014.View ArticlePubMedGoogle Scholar
  2. Raimondo G, Pollicino T, Cacciola I, Squadrito G: Occult hepatitis B virus infection. J Hepatol. 2007, 46: 160-170. 10.1016/j.jhep.2006.10.007.View ArticlePubMedGoogle Scholar
  3. Neau D, Winnock M, Galpérine T, Jouvencel AC, Castéra L, Legrand E, Tranchant E, Balestre E, Lacoste D, Ragnaud JM, Dupon M, Lafon ME, Dabis F, for the Grupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA): Isolated antibodies against the core antigen of hepatitis B virus in HIV-infected patients. HIV Med. 2004, 5: 171-173. 10.1111/j.1468-1293.2004.00206.x.View ArticlePubMedGoogle Scholar
  4. Pérez-Rodríguez MT, Sopeña P, Crespo M, Rivera A, Gonzáles del Blanco T, Ocampo A, Martínez-Vázquez C: Clinical significance of "anti-HBc alone" in human immunodeficiency virus-positive patients. World J Gastroenterol. 2009, 15: 1237-1241. 10.3748/wjg.15.1237.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Morsica G, Ancarani F, Bagaglio S, Maracci M, Cicconi P, Cozzi Lepri A, Antonucci G, Bruno R, Santantonio T, Tacconi L, Baldelli F, Piscopo R, Santoro D, Lazzarin A, D'Arminio Monforte A, for the HepaICONA and the ICONA Study Groups: Occult hepatitis B virus infection in a cohort of HIV-positive patients: correlation with hepatitis C virus infection, virological and immunological features. Infection. 2009, 37: 445-449. 10.1007/s15010-008-8194-9.View ArticlePubMedGoogle Scholar
  6. Lo Re V, Frank I, Gross R, Dockter J, Linnen JM, Giachetti C, Tebas P, Stern J, Synnestvedt M, Russell Localio A, Kostman JR, Strom BL: Prevalence, risk factors, and outcomes of occult hepatitis B virus infection among HIV-infected patients. J AIDS. 2007, 44: 315-320.Google Scholar
  7. Jardim RN, Gonzales NS, Pereira JS, Fais VC, Gonzales Junior FL: Occult hepatitis B virus infection in immunocompromised patients. Braz J Infect Dis. 2008, 12: 300-305.View ArticlePubMedGoogle Scholar
  8. Kusumoto S, Tanaka Y, Mizokami M, Ueda R: Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma. Int J STD AIDS. 2009, 20: 336-338. 10.1258/ijsa.2008.008377.View ArticleGoogle Scholar
  9. Bellini C, Keiser O, Chave JP, Evison J, Fehr J, Kaiser L, Weber R, Vernazza P, Bernasconi E, Telenti A, Cavassini M, Swiss HIV Cohort Study: Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort Study. HIV Med. 2009, 10: 12-18. 10.1111/j.1468-1293.2008.00646.x.View ArticlePubMedGoogle Scholar
  10. Chamorro AJ, Casado JL, Bellido D, Moreno S: Reactivation of hepatitis B in an HIV-infected patient with antibodies against hepatitis B core antigen as the only serological marker. Eur J Clin Microbiol Infect Dis. 2005, 24: 492-494. 10.1007/s10096-005-1355-1.View ArticlePubMedGoogle Scholar
  11. Clark SJ, Creighton S, Horner M, Smith HM, Portmann B, Taylor C, Cramp ME: Reactivation of latent hepatitis B virus infection with HIV-related immunosuppression. Int J Int J STD AIDS. 2006, 17: 67-69. 10.1258/095646206775220612.View ArticleGoogle Scholar
  12. Bagaglio S, Porrino L, Lazzarin A, Morsica G: Molecular characterization of occult and overt hepatitis B (HBV) infection in an HIV-infected person with reactivation of HBV after antiretroviral treatment interruption. Infection. 2010, 38: 417-421. 10.1007/s15010-010-0032-1.View ArticlePubMedGoogle Scholar
  13. Soriano V, Vispo E, Bottecchia M, Sheldon J, Tuma P, Garcia-Samaniego J, Barreiro P: Management of hepatitis B virus co-infection on and off antiretroviral therapy. Curr HIV/AIDS Rep. 2008, 5: 86-93. 10.1007/s11904-008-0014-4.View ArticlePubMedGoogle Scholar
  14. Martín-Carbonero L, Teixeira T, Poveda E, Plaza Z, Vispo E, González-Lahoz J, Soriano V: Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. AIDS. 2011, 25: 73-79. 10.1097/QAD.0b013e328340fde2.View ArticlePubMedGoogle Scholar
  15. Bhattacharya S, Ijaz S, Ratnaraja N, Smith S, Osmana H, Boxall E: Hepatitis B virus reactivation in a large haemodialysis unit: Virological and infection control issues. J Clin Virol. 2009, 46: 101-103. 10.1016/j.jcv.2009.05.037.View ArticlePubMedGoogle Scholar
  16. Bani-Sadr F, Maillard A, Ponscarme D, Scieux C, Molina JM: Reactivation of HBV replication in HIV-HBV infected patients. Am J Med. 2003, 114: 768-769.View ArticlePubMedGoogle Scholar
  17. Yuki N, Nagaoka T, Yamashiro M, Mochizuki K, Kaneko A, Yamamoto K, Omura M, Hikiji K, Kato M: Long-term histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology. 2003, 37: 1172-1179. 10.1053/jhep.2003.50171.View ArticlePubMedGoogle Scholar
  18. Blackberg J, Kidd-Ljunggren K: Occult hepatitis B virus after acute selflimited infection persisting for 30 years without sequence variation. J Hepatol. 2000, 33: 992-997. 10.1016/S0168-8278(00)80134-8.View ArticlePubMedGoogle Scholar
  19. Locarnini S: Hepatitis B viral resistance: mechanisms and diagnosis. J Hepatol. 2003, 39 (suppl): 124-132.View ArticleGoogle Scholar
  20. Coleman PF: Detecting hepatitis B surface antigen mutants. EID. 2006, 12: 198-203.Google Scholar
  21. Bock CT, Tillmann HL, Torresi J, Klempnauer J, Locarnini S, Manns MP, Trautwein C: Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation. Gastroenterol. 2002, 122: 264-273. 10.1053/gast.2002.31015.View ArticleGoogle Scholar
  22. Pondé RA: The underlying mechanisms for the "simultaneous HBsAg and anti-HBs serological profile". Eur J Microbiol Infect Dis. 2011,Google Scholar
  23. Cohen Stuart JV, Velema M, Schuurman R, Boucher CA, Hoepelman AI: Occult hepatitis B in persons infected with HIV is associated with low CD4 counts and resolves during antiretroviral therapy. J Med Virol. 2009, 8: 441-445.View ArticleGoogle Scholar
  24. Tsui JI, Frennch AL, Seaberg EC, Augenbraun M, Nowicki M, Peters M, Tien PC: Prevalence and long-term effects of occult hepatitis B virus infection in HIV-infected women. Clin Infect Dis. 2007, 45: 736-740. 10.1086/520989.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Zerbini A, Pilli M, Boni C, Fisicaro P, Penna A, Di Vincenzo P, Giuberti T, Orlandini A, Raffa G, Pollicino T, Raimondo G, Ferrari C, Missale G: The characteristics of the cell-mediated immune response identify different profiles of occult hepatitis B virus infection. Gastroenterol. 2008, 134: 1470-1481. 10.1053/j.gastro.2008.02.017.View ArticleGoogle Scholar
  26. Stuyver LJ, Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, Schinazi RF: Nomenclature for antiviral-resistant hepatitis B virus mutations inthe polymerase region. Hepatology. 2001, 33: 751-757. 10.1053/jhep.2001.22166.View ArticlePubMedGoogle Scholar
  27. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/310/prepub

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© Costantini et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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