Effect of HIV Immunosuppression on Response to Hepatitis B and HBV Evolution

By Liz Highleyman

Due 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.

At 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.

On average, 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 D.

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.

Results

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 HBsAg.

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.

Based 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 mutations."

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.

4/3/09

References

V 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. Abstract 99.

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.