Journal of Hepatology 44 (2006) S25–S27

www.elsevier.com/locate/jhep

Influence of viral hepatitis on HIV infection

Jürgen Kurt Rockstroh*
Department of Medicine I, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany

The natural history of HBV is known to be complicated by HIV-co-infection. In contrast, the effect of HBV on the
outcome of patients infected with HIV-1 is controversial. Some cohort studies from the pre-HAART era described a
more rapid progression to AIDS in patients carrying antibodies to the core-antigen or having chronic HBV infection,
but post-HAART studies did not detect any impact of HBV co-infection on HIV-disease progression. Similarly, studies
assessing the impact of HCV on progression of HIV-disease delivered conflicting results. In the Swiss cohort study, the
presence of HCV was independently associated with an increased risk of progression to AIDS and death. Subsequent
studies, however, did not find any difference in survival. Most interestingly, the EuroSIDA cohort analysis found no
difference between HCV-positive and HCV-negative HIV-patients starting HAART in the time needed to decrease viral
loads to less than 400 copies as well as in the time needed to increase CD4-counts by 50%. In summary, there are no
major differences in HIV-related mortality between hepatitis B or C co-infected individuals and patients infected with
HIV alone, particularly if antiretroviral treatment is given. There is, however, an increased risk of liver disease related
morbidity and mortality as well as more hepatoxicity under antiretroviral treatment regimens.
q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Hepatitis C; Hepatitis B; HIV; Co-infection

1. Introduction 2. Is HBV a co-factor for HIV-disease progression?

Since the decline in HIV-related morbidity and mortality In the setting of chronic hepatitis B, a persistent state of
after the introduction of highly active antiretroviral therapy immune activation has been described in patients with
(HAART) in 1996, liver disease caused by chronic infection chronic HBV replication possibly upregulating HIV-replica-
with hepatitis B or C virus has become an increasingly tion. Moreover, it has been suggested that the HBV X-protein
important cause of morbidity and mortality among HIV- (HBx) superinduces ongoing HIV-1 replication and HIV-1
infected patients. One third of HIV-infected individuals in long-term repeated transcription by synergizing with tat-
Europe and the USA have HCV-co-infection, and up to 10% protein and with T-cell activation signals [1]. These findings
have HBV-co-infection. HIV accelerates HBV and HCV indicate that HBx could contribute to a faster progression to
liver disease especially when HIV-associated immuno- AIDS in HBV/HIV-co-infected individuals. Indeed some of
deficiency progresses. Studies on the influence of hepatitis the early cohort studies from the pre-HAART-era described a
on progression of HIV-disease, however, have delivered more rapid progression to AIDS in patients carrying
conflicting results. In the following review, the findings antibodies to the core-antigen or having chronic HBV
and results from trials examining the impact of hepatitis infection [2,3]. Within one of these studies 232 HIV-infected
co-infection on the course of HIV are summarized and patients (age 37C8 years; CD4-count 167C167/ml; 46% had
AIDS) were investigated. Blood samples of the patients were
discussed.
investigated for markers of HBV and HCV infection (HBs-
Ag, HBe-Ag, HBV-RNA, anti-HBs, anti-HBC, anti-HCV,
HCV-RNA). Overall, 60 of 232 patients (23%) were anti-
HCV-positive, 28% of these seropositive for HCV-RNA.
* Tel.: C49 228 287 6558; fax: C49 228 287 5034. 22/232 (9%) suffered from chronic HBV-infection (HBs-Ag
E-mail address: rockstroh@uni-bonn.de (J.K. Rockstroh). positive), 18/22 (82%) of these had detectable HBe-Ag and
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2005.11.007
S26 J.K. Rockstroh / Journal of Hepatology 44 (2006) S25–S27

19/22 (86%) HBV-DNA. Presence of HCV-RNA, HBe-Ag HIV–HBV subgroups from week 4 up to week 48. Mean
and amount of HBV-RNA were related to the degree of increases in CD4 cell count were significantly lower among
immune deficiency. In contrast to the control group without HIV–HBV subgroups at week 4 (HIV, 62 cells/ml; HIV–
HBV- or HCV-infection patients infected with HIV and HBV, 29 cells/ml), however, by week 48 CD4 cell increases
either HBV or HCV showed a direct correlation between the were similar (HIV, 115 cells/ml; HIV–HBV, 113 cells/ml).
reduction of CD4-counts and decreased cholinesterase Estimated progression to AIDS event or death at week 48
activity. In patients with AIDS, co-infection with HBV or was 3.3% (95% confidence interval, 2.0–5.1%) for HIV and
HCV was associated with a reduced survival compared to 6.7% (2.5–14.6%) for HIV–HBV. The authors concluded
controls (HBV: 212 days, 95% CI: 106–317; HCV: 267 days, that an early delayed CD4-count recovery among HIV/HBV
95% CI: 112–396; controls: 439 days, 95% CI: 364–513). co-infected patients was not sustained, and was not
As liver disease associated with HBV- or HCV-co- associated with increased HIV-disease progression.
infection progresses especially in the setting of progressive There are some reports on an increased risk for
immune deficiency some of the deaths may be attributed to virological failure, development of hepatitis and hepatic
liver-related disease rather than deriving from a more rapid decompensation and death in HIV/HBV co-infected
HIV-disease. individuals after commencement of HAART therapy [10].
Other studies from the pre-HAART era, however, were It was, however, noteworthy that immunological response
not able to demonstrate a significant impact of HBV (increase in CD4-count) as well as development of new
carriage on HIV-disease progression [4–7]. In a study on AIDS-defining events was similar between HIV and HIV/
4498 homosexual participants from the Multicenter AIDS HBV-co-infected individuals. The higher virological failure
Cohort Study men were classified according to previous rate is most likely the result of a higher treatment
infection with HBV and prevalent or incident infection with interruption rate due to hepatotoxicity and flare of HBV.
HIV-1 [7]. Positivity for HBV-infection on entry was not As the median CD4-count upon HAART initiation was
related to initially low or more rapid subsequent decline in !50 cells/ml this may explain why the rate of liver disease
T-helper lymphocyte counts and was not associated with an associated morbidity and mortality was so high within this
increased incidence of AIDS during 2.5 years of follow-up. study.
Indeed the authors concluded that prior HBV-infection in
their study was unrelated to more rapid progression of HIV-
1 induced immune deficiency. More recent data from the 3. Is HCV a co-factor for HIV-disease progression?
EuroSIDA cohort found the incidence of a new AIDS-
defining event to be similar between HBs-Ag positive The issue of whether HCV also effects progression of
patients and negative patients [7,8]. After adjustment for HIV-disease remains controversial [11–17]. In the Swiss
confounding factors (use of HAART, baseline viral loads, Cohort, the presence of HCV was independently associated
CD4-cell counts, age, race, and risk factor for transmission with an increased risk of progression to AIDS and death [9].
of HIV) in a multivariate analysis, the incidence rate ratio of The increased risk was mainly attributable to lesser recovery
developing new AIDS events was again similar for the HBs- in CD4-cell counts 1 year after the start of HAART in HIV/
Ag positive group compared with the negative group. HCV-co-infected than in HCV-negative individuals. Simi-
Interestingly, the time for patients to reach undetectable lar results were also reported from some other smaller
viral loads (!400 copies/ml) or a 50% increase in CD4- cohorts [12,13]. Subsequent studies from other cohorts,
counts after 6–12 months of HAART were the same in both, however, did not find any differences in survival when
HBs-Ag positive and negative groups [7,8]. In contrast, all multivariate analysis was applied to correct for use of
cause mortality was higher for HBs-Ag positive patients HAART, baseline viral loads, CD4-cell counts, age, race,
compared to HBs-Ag negative patients. HBs-Ag positive and risk factor for transmission of HIV [7,15–17]. The
individuals were also more likely to die from liver-related EuroSIDA cohort found no difference between HCV-
disease than HBs-Ag negative patients. positive and HCV-negative HIV-infected patients respond-
These findings were recently reinforced by a study ing to newly initiated HAART with regard to time to
examining the impact of viral hepatitis co-infection on HIV- achieve an HIV-RNA !400 copies/ml or the time for CD4-
disease outcomes following commencement of combination cell counts to increase by 50%. Interestingly, recent 4-year
antiretroviral therapy in a developing country setting [9]. follow-up data from the Swiss HIV Cohort Study could not
HIV-RNA suppression, CD4 cell count recovery, and HIV- find any significant differences with regard to recovery of
disease progression were examined within a cohort of Thai CD4-cell counts between HCV-positive and HCV-negative
HIV-infected patients enrolled in eight HIV-NAT random- patients [18].
ized controlled trials of antiretroviral therapy (nZ692). Looking at the controversial results the question remains
Prevalence of HBV, HCV and HBV/HCV-co-infection was why different observations have been made and which
8.7, 7.2 and 0.4% of patients, respectively. factors may possibly contribute to these divergent findings.
Interestingly, median HIV-RNA reductions (log10 First of all, differences in adherence and the lack of tools to
copies/ml) were approximately 1.5 for HIV as well as for adequately measure adherence have to be taken into
 J.K. Rockstroh / Journal of Hepatology 44 (2006) S25–S27 S27

consideration especially in this predominantly IVDU [4] Gilson RJ, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M,
population. Moreover, in most studies, information on et al. Interactions between HIV and hepatitis B virus in homosexual
men: effects on the natural history of infection. AIDS 1997;11:
continuous drug abuse is missing. Furthermore, differences
597–606.
in the type of HAART being applied as well as treatment [5] Sinicco A, Raiteri R, Sciandra M, Bertone C, Lingua A, Salassa B,
history may have had an impact (i.e. differences in the use of et al. Co-infection and superinfection of hepatitis B virus in patients
AZT, prior NRTI mono- or dual therapy). Also there are infected with human immunodeficiency virus: no evidence of faster
some differences with regard to death event analysis. Some progression to AIDS. Scand J Infect Dis 1997;29:111–115.
cohorts have looked at overall death, others specifically at [6] Solomon RE, van Raden M, Kaslow RA, Lyter D, Visscher B,
Farzadegan H, et al. Association of hepatitis B surface antigen and co-
HIV-related deaths. Clearly, with ongoing duration of co-
antibody with acquisition and manifestations of human immuno-
infection the risk for liver death increases thereby possibly deficiency virus type 1 (HIV-1) infection. Am J Public Health 1990;
having an effect on overall mortality but not necessarily on 80:1475–1478.
HIV-disease related mortality. Finally, cohorts have mainly [7] Rockstroh J, Konopnicki D, Soriano V, Kirk O, Antunes F, Knysz B,
looked at the increase in absolute CD4-count after initiation et al. Hepatitis B and hepatitis C in the EuroSIDA cohort: prevalence
of HAART. In the co-infected individual, however, possibly and effect on mortality, AIDS, progression and response to HAART.
the initially blunted recovery of CD4-counts may be due to 11th conference on retroviruses and opportunistic infections, San
Francisco, CA, USA, Feb 8–11; 2004 [Abstract 799].
the overall lower white blood cell count as a sequelae of [8] Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B,
more advanced liver disease and hypersplenism. Here, Katlama C, et al. For the EuroSIDA group. Hepatitis B in HIV:
further analysis looking at the gain in relative percentage of prevalence, AIDS progression, response to highly active antiretroviral
CD4-counts are needed to see whether there is a true effect therapy and increased mortality in the EuroSIDA cohort. AIDS 2005;
on CD4-cell recovery in HCV-co-infected versus non-co- 19:593–601.
infected patients. [9] Law WP, Duncombe CJ, Mahanontharit A, Boyd MA,
Ruxrungtham K, Lange JM, et al. Impact of viral hepatitis co-
infection on response to antiretroviral therapy and HIV disease
progression in the HIV–NAT cohort. AIDS 2004;18:1169–1177.
4. Conclusions [10] Sheng WH, Chen MY, Hsieh SM, Hsiao CF, Wang JT, Hung CC,
et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes
In summary, extended follow-up in patients with of patients infected with HIV in an area where HBV infection is
HAART suggests that there do not exist any major hyperendemic. Clin Infect Dis 2004;15:1471–1477.
[11] Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H,
differences in HIV-related mortality between hepatitis B
et al. Clinical progression, survival and immune recovery during
or C co-infected individuals and patients infected with HIV antiretroviral therapy in patients with HIV-1 and hepatitis C virus co-
alone, particularly if antiretroviral treatment is given. There infection. Lancet 2000;356:1800–1805.
is, however, an increased risk for liver disease related [12] De Luca A, Bugarini R, Lepri AC, Puoti M, Girardi E, Antinori A,
morbidity and mortality as well as global mortality in et al. Co-infection with hepatitis viruses and outcome of initial
hepatitis co-infected HIV-patients as well as a higher risk antiretroviral regimens in previously naive HIV-infected subjects.
Arch Intern Med 2002;162:2125–2132.
for hepatoxicity under antiretroviral treatment regimens.
[13] Piroth L, Grappin M, Cuzin L, Mouton Y, Bouchard O, Raffi F, et al.
The initial CD4-count recovery may be blunted in the early Hepatitis C virus co-infection is a negative prognostic factor for
weeks after HAART initiation but becomes comparable clinical evolution in human immunodeficiency virus-positive patients.
over time between HIV and HIV/HCV-co-infected J Viral Hepat 2000;7:302–308.
individuals. [14] Lincoln D, Petoumenos K, Dore GJ. Australian HIV observational
database. HIV/HBV and HIV/HCV co-infection, and outcomes
following highly active antiretroviral therapy. HIV Med 2003;4:
241–249.
References
[15] Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL.
Hepatitis C and progression of HIV-disease. J Am Med Assoc 2002;
[1] Gomez-Gonzalo M, Carretero M, Rullas J, Lara-Pezzi E, Aramburu J, 288:199–206.
Berkhout B, et al. The hepatitis B virus X-protein induces HIV-1 [16] Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with
replication and transcription in synergy with T-cell activation signals: HIV infection and viral hepatitis B or C: a cohort study. AIDS 2004;
functional roles of NF-kappa B/NF-AT and SP1-binding sites in the
18:2039–2045.
HIV-1 long-terminal repeat promoter. J Biol Chem 2001;276:
[17] Amin J, Kaye M, Skidmore S, Pillay D, Cooper DA, Dore GJ. HIV
35435–35443.
and hepatitis C co-infection within the CAESAR study. HIV Med
[2] Eskild A, Magnus P, Petersen G, Sohlberg C, Jensen F, Kittelsen P,
2004;5:174–179.
et al. Hepatitis B antibodies in HIV-infected homosexual men are
[18] Kaufmann GR, Perrin L, Panteleo G, Opravil M, Furrer H, Telenti A,
associated with more rapid progression to AIDS. AIDS 1992;6:
571–574. et al. For the swiss HIV cohort study group. CD4-T-lymphocyte
[3] Ockenga J, Tillmann HL, Trautwein C, Stoll M, Manns MP, recovery in individuals with advanced HIV-1 infection receiving
Schmidt RE. Hepatitis B and C in HIV-infected patients. Prevalence potent antiretroviral therapy for four years. Arch Intern Med 2003;
and prognostic value. J Hepatol 1997;27:18–24. 163:2187–2195.