of HIV Immunosuppression on Response to Hepatitis B and HBV Evolution
to overlapping transmission routes, many HIV
positive individuals are coinfected with hepatitis
B virus (HBV). But the effects of HIV-related immune suppression on hepatitis
B natural history and disease progression are not well understood.
both the 16th Conference on Retroviruses and Opportunistic
Infections (CROI 2009) in Montreal in February and the 7th European HIV Drug
Resistance Workshop last week in Stockholm, Valentina Svicher and colleagues from
the Italian ICONA Study Group presented findings from their investigation comparing
HBV genetic variability in HBV monoinfected
and HIV-HBV coinfected individuals
with different levels of immunosuppression.
The investigators analyzed
full-length sequences of HBV reverse transcriptase (RT) and hepatitis B surface
antigen (HBsAg) genetic material from 30 HBV monoinfected and 31 coinfected patients,
none of whom had been treated for either HIV or hepatitis B.
the HBV monoinfected patients were considerably older than the coinfected group
(59 versus 40 years). All HBV monoinfected participants had HBV genotype D, while
most (87%) of the coinfected patients had genotype A and only 13% had genotype
HBV genetic variability was determined by calculating the entropy and
the non-synonymous/synonymous substitution (dN/dS) ratio for the entire sequence
and for each position in RT and HBsAg.
HBV monoinfected patients had a median HBV DNA level of about 4 log IU/mL, compared
with about 4.5 log for HIV-HBV coinfected patients.
There was a positive correlation between the extent of HBV RT (r 0.56; P = 0.0001)
and HBsAg (r 0.57; P = 0.0006) genetic variability and CD4 count.
In particular, HBV monoinfected and HIV-HBV coinfected patients with a CD4 count
> 600 cells/mm3 had the highest degree of genetic variability both in RT (median
entropy 0.20) and HBsAg (median entropy 0.20) sequences.
At this level of immune suppression, the median number of RT mutations was 9 and
the median number of HBsAg mutations was 8.
HBV RT and HBsAg genetic variability progressively declined as CD4 count decreased.
Within the 300-600 cells/mm3 range, the median entropy was 0.09 for both RT and
HBV genetic variability was least extensive among HIV-HBV coinfected patients
with a CD4 count of < 300 copies/mL, with RT and HBsAg median entropy of 0.00,
and a median 0 mutations.
In a multivariate analysis adjusting for age, sex, HBV genotype, hepatitis B "e"
antigen (HBeAg) status, and HIV status, there was a significant independent association
between CD4 count and number of RT and HBsAg mutations (P = 0.002 and 0.001, respectively).
dN/dS analysis showed that both HBV monoinfected and HIV-HBV coinfected patients
with CD4 counts > 600 cells/mm3 had some unique mutations in the HBsAg a-determinant
(crucial for antibody binding) and in certain cytotoxic T-lymphocyte RT epitopes.
on these results, the investigators concluded, "Our study highlights that
HIV-related dysfunction down-regulates the immune system driven selection of RT
and HBsAg mutations in drug-naive patients."
"This can accelerate
HBV disease progression and thus [increase] the risk of liver-related mortality
also in patients with moderate immunosuppression," they added. "Unique
mutations under positive selective pressure can represent new immune/vaccine escape
Discussing these findings, Svicher noted that the observed
"blunting" of HBV variability was "paradoxical," as it might
be expected that HBV would develop more mutations if it is able to replicate freely
in people with severely suppressed immune function. Instead, it appears that selective
pressure in people with fairly well-preserved immune function encourages the emergence
of more HBV mutations in an attempt to evade immune system control.
Svicher, M Trignetti, C Gori, and others. HIV-driven Immunosuppression Regulates
HBV Evolution in HBV/HIV-co-infected Patients. 16th Conference on Retroviruses
and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009.
V Svicher, C Gori, R Salpini, and others. HIV-driven immune-suppression
modulates HBV evolution in HBV+HIV co-infected patients. 7th European HIV Drug
Resistance Workshop. Stockholm, Sweden. March 25-27, 2009. Abstract 37.