Hepatitis B reverse seroconversion in HIV-positive patients: case series and review of the literature
Rouphael, Nadine Ga; Talati, Naasha Ja; Rimland, Davida,b
aDivision of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
bAtlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.
Received 12 July, 2006
Revised 18 October, 2006
Accepted 9 November, 2006
Hepatitis B (HBV) reverse seroconversion is rare in HIV disease but can be fatal. We present a case series of 6 patients with reverse seroconversion and review 18 additional cases described in the literature. Elevated transaminases were seen in 13/21 (62%). Reverse seroconversion occurred more frequently in the setting of HIV virologic failure. Only 3 patients demonstrated reverse seroconversion in the setting of lamivudine or tenofovir withdrawal. 2/24 (8%) patients died from their HBV flare.
The appearance of antibodies to hepatitis B surface antigen (HBsAb) and core antigen (HBsAb) has been considered as serological evidence of resolved infection with the clearance of hepatitis B virus (HBV). HBV serology is dynamic, however, and loss of immunity with the reappearance of HBV surface antigen (HBsAg) has been documented. This phenomenon has been termed reverse seroconversion; its significance in HIV-positive patients is unknown.
We describe the largest case series in the literature of six patients with hepatitis B virus reverse seroconversion from our HIV Atlanta Veterans' Affairs Cohort Study. We found 1957 patients from the cohort study in whom HBV serologies were available; 696 (36%) were exposed and immune. It is not clear why 229 patients had repeat serologies determined despite being exposed and immune to HBV; six underwent reverse seroconversion, accounting for 0.019 cases per 100 person-years.
Using the Medline search engine with the following search words ‘hepatitis B’ and ‘HIV’ combined with either ‘reverse seroconversion’, ‘reactivation’, ‘reinfection’ or ‘markers’, we found 18 case reports published in 13 articles [1–13]. We analysed the data on all 24 patients and describe the clinical features related to reverse seroconversion in HIV patients (Table 1). We included all these cases even though some of them lacked complete clinical data. When available, the following parameters before and after reverse seroconversion were collected: CD4 cell count, CD4 cell percentage, HIV viral load, HIV therapy, liver transaminases (aspartate transaminase, normal range 8–40 IU/l; alanine transaminase, normal range 3–36 IU/l), HBsAg, HBsAb, HBcAb, hepatitis B e antigen, antibody to hepatitis B e antigen, HBV viral load (HBV DNA) and hepatitis A, C and D serologies. A change in the CD4 cell count was defined as a change by 30% in the total CD4 cell count or more than a 3% change in the CD4 cell percentage.
All but four patients had a positive confirmatory HBV DNA. All patients were men. The median age was 43 years (19–80). Death occurred in two cases (8%) as a result of HBV flare. Three out of 14 (21%) had a positive serology for hepatitis C and only one out of 16 (6%) had hepatitis D. Elevated transaminases were observed in 13 out of 21 patients (62%). Nine out of 20 patients (45%) had a decline in the CD4 cell count, six out of 20 (30%) had no change and five out of 20 (25%) had increasing CD4 cell counts at the time of reverse seroconversion when compared with previous CD4 cell numbers and percentages obtained when the HBsAg was last negative. In our case series, the HIV viral load varied between 184 and 482 000 copies/ml. We found one report of reverse seroconversion after lamivudine withdrawal  and another similar case in our series. Only one patient from our series had reverse seroconversion 2 months after tenofovir withdrawal. None of the patients were on emtricitabine. Reverse seroconversion occurred in one patient while on lamivudine for more than 2 years, suggesting possible HBV resistance to lamivudine. Among the patients who underwent reverse seroconversion, three were on hemodialysis, one patient was on steroids and no patient was on chemotherapy or other immunosuppressants.
Our rate of HBV reverse seroconversion (0.019 cases/100 person-years) is lower than observed in other studies (0.2 cases/100 patient-years) [9,11]. Not all of our HBV naturally immune patients underwent repeated serology and the repeated serologies were not performed at a standard interval. More frequent serological testing may have resulted in our detecting a higher rate of reverse seroconversion.
Several mechanisms have been postulated to explain the phenomenon of reverse seroconversion: reinfection, low levels of HBV replication and the failure of immune surveillance.
The most intuitive theory is reinfection . This could not be excluded in any of our patients but was ruled out by others . Immunity to HBV is, however, against various epitopes and therefore should protect from other subsequent HBV subtype infections.
HBV reactivation is another explanation for reverse seroconversion. Low levels of HBV replication in the serum or liver with negative HBsAg  is a well-described entity. Studies have shown [16,17] a detectable HBV DNA in 20% of HIV patients naturally immune to HBV. Despite being low, this level of replication (< 10 000 copies/ml) has a clinical significance in the settings of blood transfusion , organ donation  and the development of hepatocellular carcinoma .
It is also thought that resolution of acute HBV infection does not necessarily indicate eradication of infection but rather the control of residual virus particles by an efficient and persistent immune response . Both T and B-cell functions are altered in HIV infection. In the overall series, reverse seroconversion occurred in the setting of worsening CD4 cell counts in nine out of 20 patients and another three patients with a CD4 cell count of less than 100 cells/μl. HIV viral load was not suppressed in any of the six patients in our case series. The phenomenon of reverse seroconversion has also been described in transplant patients , another group with T-cell abnormalities. Waning humoral immunity to HBV in HIV patients has also been documented in studies [23,24].
A further complication of serological interpretation could be the decreased sensitivity of HBsAg in patients with mutations in the ‘a’ determinant, the main target of HBsAb. This could result from a virus selection process causing an escape from the host's immune system  and a reduction in the sensitivity of the HBsAg assays because of the S protein becoming less immunoreactive with the commercial assays . It is also possible that the inability to detect HBsAg is caused by the binding of all HBsAg to HBsAb in the form of circulating immune complexes .
The control of HBV replication relies not only on an intact immune system but also on anti-HBV therapy. The appearance of reverse seroconversion after failure or interruption of lamivudine, emtricitabine or tenofovir needs to be considered. Lamivudine-resistant mutations develop commonly after lamivudine use in HIV-positive patients , and could explain reverse seroconversion in patient no. 5.
The diagnosis of reverse seroconversion should be considered in any HIV patient who has immunity to HBV. Serial testing may be needed in HIV patients with unexplained elevated transaminases, HIV virological failure, hemodialysis, immunosuppressive drugs or with the prolonged use or discontinuation of anti-HBV-specific therapy. Prospective studies are needed to assess the magnitude of HBV reverse seroconversion in HIV.
1. Lazizi Y, Grangeot-Ketos L, Delfraissy JF, Boue F, Dubreuil P, Badur S, et al
. Reappearance of hepatitis B virus in immune patients infected with the human immunodeficiency virus type 1. J Infect Dis 1988; 158:666–667.
2. Vento S, di Perri G, Luzzati R, Cruciani M, Garofano T, Mengoli C, et al
. Clinical reactivation of hepatitis B in anti-HBs-positive patients with AIDS. Lancet 1989; 8633:332–333.
3. Maeland A, Skaug K, Storvold G. Reactivation of hepatitis B. Lancet 1989; 8646:1083.
4. Ortiz-Interian CJ, de Medina MD, Perez GO, Bourgoignie JJ, Watkins F, Velez-Robinson E, et al
. Recurrence and clearance of hepatitis B surface antigenemia in a dialysis patient infected with the human immunodeficiency virus. Am J Kidney Dis 1990; 16:154–156.
5. Vandercam B, Cornu C, Gala JL, Geubel A, Cahill M, Lamy ME. Reactivation of hepatitis B virus in a previously immune patient with human immunodeficiency virus infection. Eur J Clin Microbiol Infect Dis 1990; 9:701–702.
6. Bouslama K, Knani L, Cabane J, Picard O, Lebas J, Poupon R, et al
. Reactivation of B hepatitis in an anti-HBs positive patient in HIV co-infection [in French]. Ann Med Interne (Paris) 1991; 142:63–64.
7. Blanche P, Salmon D, Sogni P, Sicard D. Reactivation of hepatitis B in AIDS [in French]. Presse Med 1995; 24:1221.
8. Altfeld M, Rockstroh JK, Addo M, Kupfer B, Pult I, Will H, et al
. Reactivation of hepatitis B in a long-term anti-HBs-positive patient with AIDS following lamivudine withdrawal. J Hepatol 1998; 29:306–309.
9. Rodriguez-Mendez ML, Gonzalez-Quintela A, Aguilera A, Barrio E. Prevalence, patterns, and course of past hepatitis B virus infection in intravenous drug users with HIV-1 infection. Am J Gastroenterol 2000; 95:1316–1322.
10. Manegold C, Hannoun C, Wywiol A, Dietrich M, Polywka S, Chiwakata CB, et al
. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2001; 32:144–148.
11. Piroth L, Binquet C, Vergne M, Minello A, Livry C, Bour JB, et al
. The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients. J Hepatol 2002; 36:681–686.
12. Fabris P, Giordani MT, Tositti G, Rassu M, De Lalla F. Occult hepatitis B virus infection in HIV/hepatitis C virus co-infected patients. AIDS 2003; 17:1581–1582.
13. Richardson D, Lamba H. Hepatitis B infection in an HIV-positive man treated with tenofovir: a case of re-infection or reactivation? Int J STD AIDS 2004; 15:204–205.
14. Vento S, Di Perri G, Garofano T, Concia E, Bassetti D. Reactivation of hepatitis B in AIDS. Lancet 1989; 8654:108–109.
15. Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994; 93:230–239.
16. Mphahlele MJ, Lukhwareni A, Burnett RJ, Moropeng LM, Ngobeni JM. High risk of occult hepatitis B virus infection in HIV-positive patients from South Africa. J Clin Virol 2006; 35:14–20.
17. Santos EA, Yoshida CF, Rolla VC, Mendes JM, Vieira IF, Arabe J, et al
. Frequent occult hepatitis B virus infection in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2003; 22:92–98.
18. Liu CJ, Lo SC, Kao JH, Tseng PT, Lai MY, Ni YH, et al
. Transmission of occult hepatitis B virus by transfusion to adult and pediatric recipients in Taiwan. J Hepatol 2006; 44:39–46.
19. Chazouilleres O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, et al
. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994; 8890:142–146.
20. Yu MC, Yuan JM, Ross RK, Govindarajan S. Presence of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California. Hepatology 1997; 25:226–228.
21. Ferrari C, Missale G, Boni C, Urbani S. Immunopathogenesis of hepatitis B. J Hepatol 2003; 39(Suppl. 1):S36–S42.
22. Kempinska A, Kwak EJ, Angel JB. Reactivation of hepatitis B infection following allogeneic bone marrow transplantation in a hepatitis B-immune patient: case report and review of the literature. Clin Infect Dis 2005; 41:1277–1282.
23. Drake JH, Parmley RT, Britton HA. Loss of hepatitis B antibody in human immunodeficiency virus-positive hemophilia patients. Pediatr Infect Dis J 1987; 6:1051–1054.
24. Biggar RJ, Goedert JJ, Hoofnagle J. Accelerated loss of antibody to hepatitis B surface antigen among immunodeficient homosexual men infected with HIV. N Engl J Med 1987; 316:630–631.
25. Lada O, Benhamou Y, Poynard T, Thibault V. Coexistence of hepatitis B surface antigen (HBsAg) and anti-HBs antibodies in chronic hepatitis B virus carriers: influence of “a” determinant variants. J Virol 2006; 80:2968–2975.
26. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002; 2:479–486.
27. Stanojevic M, Zerjav S, Jevtovic DJ, Markovic LJ. HBsAg as the antigen component of circulating immune complexes in HIV-infected patients. Biomed Pharmacother 2000; 54:163–167.
28. Matthews GV, Bartholomeusz A, Locarnini S, Ayres A, Sasaduesz J, Seaberg E, et al
. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS 2006; 20:863–870.
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