Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B
This study was conducted before the availability of adefovir for treatment of HBV, but the study has significance because Pegasys is being studied for HBV treatment. The study was conducted also prior to HAART availability as 54 of 69 HIV+ patients in this study were taking single, double, or triple nuke therapy. Most patients were AZT monotherapy. This study offers interesting insights to the course of HBV in HIV-infected patients. Here is link to review of the study presented at 2002 Nov AASLD on Pegasys (pegylayed interferon) for treatment of HBV: http://www.natap.org/2002/AASLD/day18.htm
The outcome of chronic hepatitis B and the efficacy of interferon alfa (IFN-) remain controversial in human immunodeficiency virus (HIV)-positive patients. We analyzed the influence of HIV coinfection on the response to IFN- therapy, long-term virologic status, progression to cirrhosis, and mortality. This was a retrospective follow-up cohort study of 141 consecutive hepatitis B antigen-positive patients (69 HIV positive) followed up for 45 months. The alcohol consumption (>40 grams/day) was the same in the HIV+ and HIV- patient groups in this study. Duration of HBV was the same in HIV+ and HIV negative patient groups (33 months vs 28 months, NS). The short-term response to IFN- therapy was not significantly different in HIV-positive and HIV-negative patients (28% vs. 51%; P = 0.06) but was poorer in cases of low CD4 cell count (P = 0.038). The hepatitis B virus (HBV) reactivation rate was higher in HIV-positive patients (P = 0.033) and was associated with low CD4 cell count. The risk of cirrhosis was higher in HIV-positive patients with a CD4 cell count <200/mm3 (relative risk [RR], 4.57; P = 0.007), in IFN--untreated patients (RR, 2.63; P = 0.041), in patients older than 33 years (RR, 4.59; P = 0.008), and in cases of high necroinflammatory score at baseline (RR, 1.27; P = 0.010). Cirrhosis-related death was more frequent in HIV-positive patients with low CD4 cell count at baseline (P = 0.041), in alcohol consumers (P = 0.001), in IFN--untreated patients (P = 0.052), and in patients with high histology activity index at baseline (P = 0.005). Conclusions: HIV coinfection was associated with poorer response to IFN- therapy, more frequent HBV reactivations, and increased incidence of cirrhosis and cirrhosis-related death in cases of low CD4 count. IFN- therapy decreased the incidence of HBV cirrhosis regardless of HIV status or serologic response.
Gastroenterology; December 2002, Volume 123, Number 6
"...all of the HIV-positive responders experienced a spontaneous flare of serum ALT level during the 3-month pretherapeutic period, indicating that IFN- therapy might have only contributed to an ongoing spontaneous clearance of HBV-infected cells..."
We observed among HIV-positive patients that 24% of death was related to cirrhosis. Four of the 5 HIV-positive patients who died from cirrhosis were not deeply immunosuppressed (CDC stage A or B). This result shows that liver disease-related mortality is relatively important in HIV-HBV coinfected patients. HBV-related mortality might be reduced in HIV-infected patients receiving highly active antiretroviral therapy because immune restoration
was shown to induce HBe seroconversion and HBsAg loss.55 Moreover, as already reported in HIV-negative patients, IFN- therapy could improve survival in HIV-positive patients. Its efficiency in HBV mutants resistant to lamivudine remains to be assessed in HIV-positive patients.
The deleterious impact of HIV-related immunodepression on the course of chronic hepatitis B may be surprising when considering that the cellular immune response has been identified as the main pathogenic factor for liver necroinflammatory lesions in chronic hepatitis B. However, the mechanism of fibrosis progression may observe different rules and may be strongly accelerated in cases of immunosuppression. This has been shown for chronic hepatitis C in HIV-infected individuals. In another immunosuppressed population (liver graft recipients), recurrence of HBV is associated with rapid progression to cirrhosis. One hypothesis is that a high level of HBV replication related to immunosuppression may induce accumulation of viral proteins and a direct cytopathogenic effect. Other hypotheses include the role of the immune defect on the function of Kupffer cells and the TH1/TH2 cytokine imbalance resulting in the enhancement of liver fibrosis.
There are an estimated 300 million hepatitis B virus (HBV) carriers and 30-40 million human immunodeficiency virus (HIV)-infected patients worldwide. HBV
and HIV-1 coinfection is frequently observed because these 2 viruses share the same epidemiology in route of transmission, risk groups involved, and chronicity of disease. Because molecular interactions between theses 2 viruses were described and because HIV may compromise the immune status of infected patients, the natural outcome of chronic hepatitis B might be different in HIV-positive than in HIV-negative patients. Indeed, some studies found that cirrhosis occurred more frequently in HIV-positive patients than in HIV-negative patients and that HIV infection seemed to worsen the outcome of chronic hepatitis B with a higher mortality rate. Lamivudine, commonly used as therapy for HIV-HBV coinfected patients, was recently reported to induce HBV-escape mutants with a 5-year actuarial rate close to 100% in HIV-infected patients,7 underlying the need for additional therapies. Interferon alfa (IFN-) therapy, which induces a sustained inhibition of HBV replication in about one third of HIV-negative patients, has been reported to be little effective in HIV-positive patients. However, its low efficacy has never been clearly assessed because few data on the response to IFN- therapy are available in HIV-HBV coinfected patients from studies with small numbers of patients. Because of the small numbers of cases included and the short follow-up of the studies, definitive conclusions about the influence of HIV both on the natural history of chronic hepatitis B and the response to IFN- therapy are still missing.
The aim of this study was to compare the response of HIV-positive and HIV-negative patients to IFN- therapy and its impact on long-term virologic outcome of HBV infection, progression to cirrhosis, and survival.
Serum HBV DNA levels were higher in HIV-positive patients than in HIV-negative patients (283 ± 271 vs. 158 ± 160 pg/mL; P = 0.014), a finding consistent with that previously reported. Increase of HBV replication is probably the
consequence of HIV-related immunodepression. Indeed, multivariate analysis found a negative correlation between the CD4 cell count and serum HBV DNA
level. Multivariate analysis also indicated, as previously reported in HIV-negative patients,24 a negative correlation between estimated duration of HBV
infection and serum HBV DNA level in HIV-infected patients.
Three factors were associated with worse fibrosis: age (p=0.009), alcohol consumption >40 grams/day (p=0.039), serum HBV-DNA (p=0.008).
Impact of HIV coinfection on the response to IFN- therapy and the outcome of chronic hepatitis B
Virologic and serologic response to IFN- therapy During IFN- therapy and within the 6 months following the end of IFN- therapy, loss of serum HBV DNA occurred in 7 of 26 treated HIV-positive patients and 28 of 50 treated HIV-negative patients (27% vs. 56%; NS). Short-term HBe seroconversion occurred in 3 HIV-positive patients and 14 HIV-negative patients (11.5% vs. 28%; NS). The HIV-positive patients who responded had the following characteristics compared with those who did not respond: higher pretreatment CD4 lymphocyte count (566 ± 258 vs. 320 ± 200; P = 0.038), higher Knodell score (14 ± 4.2 vs. 7.5 ± 3.8; P = 0.047), and higher pretreatment serum ALT level
(10.5 ± 4.5 vs. 3.0 ± 2.8; P = 0.007). Indeed, before starting IFN- therapy, a spontaneous significant elevation of serum ALT level was observed in the
responders. Age, estimated duration of HBV infection, serum HBV DNA level, proportion of alcohol consumers, and histologic fibrosis were not different between HIV-positive responders and HIV-positive nonresponders. Hepatitis B surface seroconversion occurred in one HIV-positive and 5 HIV-negative patients (3.8% vs. 10%; NS).
HBe seroconversion in untreated patients
HBe seroconversion occurred in 17 of the 65 patients (Table 4); it concerned 10 of 43 (23.3%) HIV-positive untreated patients and 7 of 22 (31.8%)
HIV-negative untreated patients (NS). The actuarial spontaneous HBe seroconversion rate was not significantly different according to HIV status. Among the 43 untreated HIV-positive patients, a low CD4 cell count at baseline was significantly correlated with a low spontaneous HBe seroconversion rate in the long term (Cox; P = 0.049). Through univariate analyses, the spontaneous HBe seroconversion rate was higher in patients with low serum HBV DNA level (90 ± 126 vs. 318 ± 279; P = 0.007) and higher serum ALT level (3.8 ± 2.2 vs. 2.9 ± 1.9; P = 0.044). In a multivariate analysis (Cox) considering alcohol, histology activity index, and HBV DNA level at baseline as independent variables, the histology activity index was the only factor associated with a higher spontaneous Hbe seroconversion rate (relative risk [RR], 1.20; P = 0.046).
Factors influencing HBe seroconversion
The overall HBe seroconversion rate in treated and untreated patients was 16.7% at 1 year, 25.9% at 2 years, and 31.3% at 3 years. Multivariate analysis identified 2 independent factors for subsequent HBe seroconversion: high histology activity index at baseline and IFN- therapy. HIV coinfection had no significant influence considering both treated and untreated patients.
In our study, the spontaneous loss of HBeAg was associated with a high histology activity index, suggesting the persistence of immune-mediated cytotoxicity. Overall spontaneous HBe seroconversion rates were not significantly different in HIV-positive and HIV-negative patients, a finding at variance with previous reports.28-31 However, the spontaneous HBe seroconversion rate was lower, as expected, in HIV-positive patients with a low CD4 cell count. The spontaneous loss of HBsAg seems to be extremely rare in HIV-infected patients and was not observed in any patient in our study.
The 6 patients who became HBsAg negative and antibody to hepatitis B surface antigen positive conserved this serologic status during the entire follow-up.
Among the 47 patients who experienced HBe seroconversion, a reactivation (loss of anti-HBe antibodies with reappearance of HBeAg) occurred in 8 cases with a mean delay from HBe seroconversion of 8.4 ± 2.3 months. All cases of HBV reactivation occurred during the 2 years following HBe seroconversion.
It concerned 5 of 14 (35.7%) HIV-positive patients and 3 of 33 (9%) HIV-negative patients (P = 0.036). The HBe seroreversion rate was significantly higher in
HIV-positive than in HIV-negative patients (P = 0.031).
In HIV-positive patients, the HBe seroreversion rate was 23% at 6 months, 30% at 1 year, and 39% at 2 years, whereas this rate was 10% at 1 year in
HIV-negative patients without any additional case during subsequent follow-up. In HIV-positive patients, the HBe seroreversion rate was not influenced by the
CD4 cell count measured at baseline; it was similar in patients who developed subsequent HBV reactivation compared with others (463 ± 108 vs. 440 ± 85; NS). However, HIV-positive patients who experienced HBV reactivation had a significant decrease in CD4 cell count at the time of HBV reactivation (median from 455 to 318; P = 0.033), whereas HIV-positive patients who remained anti-HBe positive had no significant variation in their CD4 cell count during a similar
period (from 440 ± 85 to 371 ± 78; NS). The other factor increasing the HBV reactivation rate was age; patients who developed HBV reactivation were older (42 ± 3.1 vs. 33 ± 1.4 years; P = 0.019). Patients with cirrhosis at inclusion developed more frequent HBV reactivation, but this trend did not reach a significant level (P = 0.068). The HBV reactivation rate was not influenced by alcohol consumption, known duration of HBV infection, and histology activity index on the last available biopsy. The HBV reactivation rate was similar in patients who previously developed spontaneous or IFN--induced HBe seroconversion. Multivariate analysis could not be performed because of the small number of cases with HBV reactivation.
A high HBV reactivation rate was observed in HIV-positive patients, consistent with that previously reported. The reappearance of HBeAg was prompt in HIV-positive patients (30% at 1 year and 39% at 2 years without any additional cases during follow-up) and was not influenced by a previous IFN- treatment.
Viral reactivation had been reported to be favored by a decrease in immunity and/or a decline in naturally acquired antibodies in HIV-infected patients.46 This was confirmed by the observation of a significant decrease in CD4 cell count in HIV-positive patients at the time of HBV reactivation. Baseline CD4 cell count was not significantly associated with subsequent occurrence of HBV reactivation, suggesting that HBV reactivation is an acute phenomenon and that the delay between the decrease in CD4 and HBV reactivation may be short. Indeed, HBV reactivation was associated with a significant decrease in CD4 cell count. Other phenomena, such as the influence of HBV subtype or the host's cytokines distribution, may thus be involved in the occurrence of HBV reactivation. HBV reactivation is commonly associated with an exacerbation of the liver disease that can be fatal, particularly in patients with cirrhosis. Such a finding was observed in one of our HIV-positive patients, whose HBV reactivation caused liver failure and death.
Progression to cirrhosis
Cirrhosis was present on the first liver biopsy in 18 patients (13%); 12 were HIV positive and 6 were HIV negative (17.4% vs. 8.3%; NS). During follow-up,
histologically proven cirrhosis occurred in 12 additional patients; 3 were HIV positive and 9 were HIV negative (5.3% vs. 13.6%; NS), with a mean delay from the first liver biopsy of 2.7 ± 0.5 years. The overall prevalence of cirrhosis at the end of follow-up was 28.4%; 15 were HIV positive and 15 were HIV negative (21.7% vs. 20.8%; NS). Through univariate analysis, the progression to cirrhosis was higher in older patients (P < 0.001), patients with a CD4 cell count <200/mm3 either at baseline (n = 15) or during follow-up (n = 10) (P = 0.005; Figure 3), patients who maintained a high serum HBV DNA level (P < 0.001), and patients who did not receive IFN- therapy (P = 0.009). The difference was not significant according to HIV status, irrespective of the level of immunodepression. In multivariate analysis, 4 variables were significantly
associated with an increased risk of progression to cirrhosis: age older than 33 years (RR, 4.59; P = 0.008), CD4 cell count <200/mm3 during follow-up (RR,
4.57; P = 0.007), high histology activity index at baseline (RR, 1.27; P = 0.010), and absence of IFN- therapy (RR, 2.63; P = 0.041).
Death occurred in 21 HIV-positive (30.4%) and 2 HIV-negative (2.8%) patients. Among the HIV-positive patients, it was related to acquired immunodeficiency
syndrome in 16 cases and to liver disease in 5 cases (coma related to liver failure in 3, spontaneous bacterial peritonitis in one, and variceal bleeding in one). One case of coma was clearly related to HBV reactivation. Four of the 5 HIV-positive patients who died from cirrhosis were A or B according to the CDC
classification system. In HIV-negative patients, one death was due to a myocardial infarction and the other was due to hepatic coma following HBV
reactivation. Considering the whole population, the actuarial rate of death related to cirrhosis was increased in alcohol consumers (P = 0.001) and in cases of high histologic index at baseline (P = 0.005); a trend was observed for HIV coinfected patients (P = 0.055) and patients who did not receive IFN- therapy (P = 0.052). Conversely, neither age nor persistence of HBeAg was significantly associated with a subsequent death related to cirrhosis. Patients who died from
cirrhosis more often had a CD4 cell count <200/mm3 at baseline; among patients who died from cirrhosis, there were 4 of 17 patients (23%) with low CD4 cell count at baseline and 1 of 52 (2%) with CD4 cell count >200/mm3 (P = 0.011).
SUMMARY/Discussion by authors
Our study provided 4 relevant findings about the outcome of chronic hepatitis B in HIV-positive patients. (1) HIV coinfection was associated with poorer response to IFN- therapy. (2) HIV coinfection was associated with more frequent HBV reactivations. (3) In HIV-infected patients, a low CD4 cell count was associated with an increased incidence of cirrhosis and cirrhosis-related death. (4) IFN- therapy decreased the incidence of HBV cirrhosis regardless of HIV status or serologic response.
In HIV-negative patients, the natural history of chronic hepatitis B is characterized by spontaneous HBe and hepatitis B surface seroconversion rates of 10% and 0.4%-2% per year in western countries, respectively, an incidence of cirrhosis of 15%-20% at 5 years, and a decrease in survival associated with
long-lasting HBeAg positivity. In HIV-positive patients, the outcome of chronic hepatitis B has not been clearly characterized. Indeed, few data on the
outcome of chronic hepatitis B in HIV-positive patients are available because large homogeneous cohorts of HIV-HBV coinfected patients who do not have
HCV or HDV coinfection are difficult to find. Moreover, in all of the previous studies, HIV-positive patients infected by HBV precore mutants (HBeAg negative) or wild-type (HBeAg positive) HBV were considered altogether. Our series provided a 4-year serologic clinical and histologic follow-up comparing 2 homogeneous groups of 69 HIV-positive and 72 HIV-negative homosexual men who were not addicted to drugs and excluded patients infected with HBV precore mutants or coinfected with HDV or HCV. One limitation of this study is that our HIV-positive patients did not receive highly active antiretroviral therapies during follow-up and thus are not representative of the present HIV-positive population. However, protease inhibitor therapies have been reported to induce hepatotoxicity and to increase virus-related liver damage.Hence, our population was more suitable to assess the direct influence of HIV coinfection on the outcome of chronic hepatitis B. In our study, although HIV-positive and HIV-negative patients were not matched, the 2 groups were not different with respect to age and alcohol consumption. Moreover, the influence of HIV coinfection on serologic and histologic features was systematically assessed through multivariate analyses to better control all putative confounding factors.
IFN- therapy was able to induce loss of serum HBV DNA and to increase HBe seroconversion rate only in HIV-negative patients. The IFN--induced HBe
seroconversion rate observed in HIV-negative patients (28%) was similar to that reported in previous series. In HIV-positive patients, the loss of HBV DNA
was obtained only in 28% of cases, consistent with that previously published; the HBe seroconversion rate (11.5%) was higher than that observed in most
of the previously published series but in accordance with other reports. We were able to identify high pretreatment serum ALT level as a good
predictor of response to IFN- therapy in HIV-infected patients as well as in HIV-negative patients as previously reported. Indeed, all of the HIV-positive
responders experienced a spontaneous flare of serum ALT level during the 3-month pretherapeutic period, indicating that IFN- therapy might have only
contributed to an ongoing spontaneous clearance of HBV-infected cells. IFN--induced hepatitis B surface seroconversion is probably a rare event but
may occur in HIV-positive patients; one case was observed in our series, and the patient maintained this serologic status during the 38-month follow-up.
The influence of HIV on HBV-related histologic lesions was mainly observed in immunocompromised patients. Although the progression to cirrhosis was not
significantly different in HIV-positive and HIV-negative patients, a low CD4 cell count during follow-up significantly increased the risk of cirrhosis. In a previous
study, we found a higher proportion of patients with cirrhosis in the HIV-positive group compared with the HIV-negative group (28% vs. 13%; P = 0.04). Thisdiscrepancy is probably caused by the different populations studied. Indeed, in the present study, we excluded the patients with precore mutant HBV (HbeAg negative) and included only patients who had more than 6 months of follow-up. In addition, we included additional patients seen in our center between 1996 and 1997. One limitation of our analysis of the incidence of cirrhosis is that repeat liver biopsy was not systematically performed in all patients; therefore, the incidence of compensated cirrhosis might have been underestimated. Indeed, systematic serial liver biopsies were not feasible for ethical reasons and repeat biopsies were performed according to clinical criteria (i.e., in those patients in whom histologic deterioration or cirrhosis was suspected). Nevertheless, the same criteria were used in the overall population regardless of HIV status or treatment.