We have shown that liver transplantation in HBV-HIV coinfected persons achieves excellent outcomes with 85% patient and graft survival after median 42 months of follow-up, and with no patient requiring re-transplantation for graft loss. Moreover, clinically apparent recurrent HBV disease was successfully prevented in all patients. These results confirm and extend the results of other smaller studies (4–8 HBV-HIV co-infected subjects each) (5
) and a larger (N=13) French series (11
), reporting 100% patient and graft survival and 0% recurrent HBV disease. Importantly, we have also shown patients that have detectable HBV DNA at the time of transplantation can achieve excellent outcomes without recurrent HBV disease when a high dose HBIG plus antiviral prophylaxis strategy is used. Based upon these results, we do not feel that there is a requirement for HBV-HIV infected patients to have an undetectable HBV DNA level to be considered transplant candidates.
Recurrent HBV infection post-LT is defined by the presence of hepatitis B surface antigen, absence of anti-HBs antibodies and measurable serum HBV DNA levels using standard clinical assays (25
). We hypothesized that HIV infected patients with HBV coinfection may be at higher risk of recurrence post-LT due to the frequency of LMV-resistance among wait-listed patients and frequent presence of detectable HBV DNA at the time of LT. However, using a combination prophylaxis approach of HBIG plus antiviral therapy, HBV recurrence was prevented during a follow-up period of up to nearly 7 years. Almost all of our patients (21/22, 95%) were on a combination of two oral anti-HBV antivirals as well as HBIG. Whether combination antiviral therapy rather than one potent antiviral drug, such as entecavir or tenofovir, are required when used in combination with HBIG is unknown. However, given the potential serious consequence of recurrent disease in the graft, a regimen of two antivirals with complementary resistance profiles may be better than a single drug. Additionally, we believe HBIG, which acts by an entirely different mechanism to prevent HBV recurrence, is also an important component of effective prophylaxis in these patients. Of course, this high-dose HBIG regimen is expensive and strategies to reduce the cost of prophylaxis by using lower doses of HBIG and intramuscular rather than intravenous administration need to be considered. Regardless, we believe that prophylactic therapy using combination antiviral therapy and HBIG is the optimal long-term method to prevent recurrent HBV infection.
Occult HBV infection has been reported in HBV monoinfected patients post-LT (14
) as well as in non-LT patients living with HIV (29
). We found that 54% of transplant recipients, with post-LT sera available, had intermittently detectable HBV viremia with absence of HBsAg and presence of anti-HBs. This suggests that HBV replication is occurring despite an aggressive prophylaxis regimen, albeit at low levels. The clinical consequences of occult HBV infection are unclear. None of the coinfected patients with occult HBV infection had any evidence of hepatitis. In contrast to our results regarding occult HBV infection, Tateo and colleagues tested coinfected liver transplant recipients and found 0/13 had detectable HBV DNA in serum or 0/9 had cccDNA in liver (11
). The reason for the very different results may be related to the virologic status of the patients at the time of LT. In the French series, all co-infected patients had undetectable HBV DNA levels at the time of transplantation, whereas in our cohort this was not a requirement. When we compared those patients in our cohort with intermittently detectable HBV DNA to those who were persistently HBV DNA negative, occult HBV infection tended to be more common in those with lower CD4 cell counts at time of viremic episode and detectable HBV DNA at time of transplantation, lower median levels of anti-HBs on HBIG therapy, and a history of treated acute rejection. An ineffective cytotoxic T-lymphocyte response and lower titers of neutralizing anti-HBs antibodies have been linked to persistent occult HBV infection in non-transplant patients (34
), Coinfected patients who are viremic at transplantation and with less than ideal immune protection may be at greatest risk for reinfection that is manifested by intermittently positive HBV DNA in serum on prophylaxis.
The HBV genome is known to have a glucocorticoid responsive element (36
). Thus, treatment of acute rejection requiring pulse steroids could explain the detection of occult HBV in some patients. This has been suggested by other studies documenting occult HBV reactivation in HBV monoinfected liver transplant recipients who received high dose steroid therapy (27
). Finally, some authors has suggested occult HBV in HIV-infected carriers could be explained by mutations within HBsAg “a” determinant that potentially interferes with the recognition of HBsAg (33
), In our study, sequencing analysis was possible only in five of seven cases with occult HBV, due to the low-level plasma DNA, but no novel surface gene escape mutants were identified.
Limitations of this study include the lack of HBV DNA testing by rtPCR in HBV monoinfected control group and the use of a very sensitive detection method which prevents comparisons with previously published studies regarding occult HBV infection (37
). Additionally, the control group was obtained from a single center rather than all the centers participating in the multicenter study. However, over 50% of the coinfected patients came from the same center as the controls. Importantly, the controls received similar HBV prophylaxis as the coinfected patients. It is of interest that at the time of LT, approximately half the subjects in each group had detectable HBV DNA by standard PCR methods, the risk factor most consistently associated risk with HBV recurrence (26
). It should be acknowledged that it is possible, although unproven, that other differences in the baseline characteristics between monoinfected and dual infected recipients may also have contributed to differences in survival and risk of recurrence. Unfortunately, the limited numbers of outcomes prevented evaluation of predictors of survival using multivariate analysis.
In summary, the outcomes in HBV-HIV coinfected patients are excellent and support the use of LT for complications of cirrhosis. Prophylaxis with combination HBIG and antiviral therapy is highly effective in preventing clinical disease, even in those with HBV DNA detectable at the time of transplantation, and we believe this represents the best strategy for prevention of recurrent HBV infection in this population. The high frequency of intermittent low-level HBV viremia emphasizes the need for life-long HBV prophylaxis to prevent recurrence of HBV infection.