Patients infected with HIV-1 are at high risk of developing hepatitis B virus (HBV) infection due to shared routes of transmission such as sexual intercourse and blood contact. More than 80% of HIV-infected patients have serological markers of active or past HBV infection, and up to 14% are coinfected with HBV.1–3
Of note, acute hepatitis B infection (AHB) resolved in 90%–95% of immune-competent individuals who acquired their infection in adulthood.4,5 In immune-compromised patients, the rate of chronicity is high, while the rates of spontaneous loss of hepatitis B e-antigen (HBeAg) and/or hepatitis B surface antigen (HBsAg) are low.6,7 In addition to the lower rate of resolution of HBV infection, in HIV-infected patients, there are faster progression of liver disease in those who become chronically infected and increased rates of liver-related death.8,9
As there is an effective vaccine available, all HIV-infected patients are advised to get vaccinated against HBV. However, many immune-deficient patients do not respond effectively to this vaccination.10,11 Furthermore, although vaccination is recommended, many patients do not receive any vaccination. In the general population, when AHB occurs, treatment is not recommended (except for severe AHB) due to the low rate of developing chronic hepatitis B infection (CBI).12 Despite the high rate of chronicity of HBV infection in HIV-infected patients, this important issue has not been sufficiently investigated in this population.
The primary aim of this study was to evaluate the frequency of CBI in HIV-1–infected patients with AHB and the rate of seroclearance for HBeAg and HBsAg during long-term therapy with dually acting antiretroviral treatment (DAART) in patients with CBI. The secondary aim was to explore the association of demographic, clinical, and laboratory factors with the progression of AHB to CBI.
In this retrospective observational study, we examined the demographic, clinical, therapeutic, and laboratory data of adult HIV-1–infected patients who had an AHB diagnosis between January 2000 and July 2016, as recorded in the database of the Division of Infectious Diseases of the San Raffaele Hospital (CSLHIV Cohort). The CSLHIV Cohort was approved by the ethics committee of the San Raffaele Hospital. On their first visit, the patients provided written informed consent for scientific analyses of their data.
The AHB diagnosis was based on documented clinical or laboratory history of AHB. A resolved AHB (RAHB) was defined as a positivity in antibodies to HBsAg recorded within 6 months after an AHB diagnosis. CBI was defined as the persistence of HBsAg in the serum, evaluated at least 6 months after an AHB diagnosis.
Demographic, clinical [time since HIV diagnosis, initiation of antiretroviral therapy (ART), and mode of exposure to HIV-1], and laboratory data at AHB diagnosis, including serological markers of HBV infection (HBsAg and HBeAg), antibodies against hepatitis C virus (anti-HCV), CD4+ T-cell count, CD8+ T-cell count, CD4+/CD8+ ratio, transaminase levels, HIV-RNA, HCV-RNA, and HBV-DNA load at AHB diagnosis when available, were evaluated. Information on HBV vaccination was also collected. The time of exposure to DAART (including lamivudine, emtricitabine, and tenofovir) within 6 months before AHB was calculated in all patients. In patients with persistence of HBsAg, the time of exposure to DAART was also calculated in the phase of chronicity.
Results were reported as medians with interquartile ranges or frequencies (%).
Characteristics of HIV-1–positive patients were compared using the χ2 or Fisher exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables.
Potential determinants for CBI were examined by applying univariate and multivariate logistic regression models; results were reported as odds ratios with corresponding 95% Wald confidence intervals (CIs). The multivariate model included characteristics with a P value of ≤0.20 in the univariate logistic regression analysis or factors that were chosen a priori as being potentially associated with CBI (HCV infection, CD4+ and CD8+ T-cell counts, DAART, and transaminase levels).13–16
All statistical tests were 2-sided at the 5% significance level (P ≤ 0.05) and were performed using SAS software (version 9.4; SAS Institute, Cary, NC).
Among 5394 subjects who were enrolled in the cohort between 2000 and 2016, 4717 had at least 6 months of follow-up. Of the 4717 HIV-1–infected patients, 63 (1.3%) had an AHB diagnosis during a median follow-up of 11.1 (4.5–17.7) years, and 23 (36.5%) of them became chronically infected after AHB. Patients' characteristics in the overall sample and according to AHB outcome (RAHB or CBI) are listed in Table 1. Patients whose infection progressed to CBI did not show any significant difference from patients with RAHB in any of the variables considered.
Regarding anti-HBV treatment, exposures to DAART before and after AHB are presented in Table 1. Of the 23 (36.5%) patients on DAART during AHB, 16 (70%) were on lamivudine and 7 (30%) on emtricitabine/tenofovir. After AHB, all 63 patients continued with or were initiated with DAART.
None of patients were vaccinated for HBV before AHB or were on a vaccination schedule at AHB diagnosis.
On univariate analysis, none of the considered variables were associated with the risk of CBI (Table 2). Meanwhile, on multivariate analysis, the risk of CBI after AHB was less likely in patients with HIV-RNA of >50 copies/mL (adjusted odds ratio [OR] = 0.03, 95% CI: 0.001 to 0.58, P = 0.021) and marginally lower for patients on DAART (lamivudine, emtricitabine, or tenofovir) (adjusted OR = 0.07, 95% CI: 0.01 to 1.02, P = 0.050).
Among the 23 patients who developed CBI, 15 (65.2%) lost HBeAg in a median time of 54 (14–101) months since AHB, and 11 of them (47.8%) also lost HBsAg in a median period of 24 (15–99) months after HBeAg seroclearance. Finally, 4 (17.4%) patients produced antibodies to HBsAg. The characteristics of patients with CBI according to seroclearance or persistence of HBeAg and HBsAg are listed in Table, Supplemental Digital Content, https://links.lww.com/QAI/B343.
Patients who lost HBeAg during follow-up had lower CD8+ T-cell count (P = 0.008) and percentage (P = 0.022) during AHB than those who maintained their HBeAg levels, while the CD4+/CD8+ ratio showed a trend toward significance (P = 0.089). The other variables examined were similarly distributed between the 2 groups.
During the last visit, the CD4+ percentage (P = 0.036) and CD4+/CD8+ ratio (P = 0.049) used to evaluate immunological status and necroinflammatory activity, respectively, were significantly higher in patients with HBeAg seroclearance. Alanine transaminase (ALT) levels were within normal range in patients with HBeAg seroclearance and above normal range (P = 0.033) in patients with persistence of HBeAg (see Tables, Supplemental Digital Content, https://links.lww.com/QAI/B343).
Comparison of characteristics during AHB between patients with and without HBsAg seroclearance during the CBI course (see Tables, Supplemental Digital Content, https://links.lww.com/QAI/B343) showed that HBsAg seroclearance was related to lower CD8+ T-cell counts (P = 0.020) and higher aspartate aminotransferase (AST) levels (P = 0.043).
In this study, we analyzed the clinical findings of a group of HIV-1–infected patients with AHB and the possible factors predicting the outcome of AHB.
Our findings confirm those of earlier studies14,17–19 that were performed in smaller groups of HIV-1–infected patients and that investigated about the high frequency of CBI after AHB. In the study by Bodsworth et al,14 which included 31 HIV-1–infected subjects with AHB, 23% (7/31) of patients developed CBI. In the studies by Sinicco et al17 and van Houdt et al,18 which evaluated 15 and 47 AHB cases, respectively, a higher frequency of CBI (40%) was detected. Moreover, in the study by Hadler et al,19 AHB progressed to CBI in 3 of 14 patients (21%).
Regarding immune status during AHB, Bodsworth et al14 showed that a higher CD4+ T-cell count at baseline was associated with the outcome of “resolved HBV infection.” However, this finding was not confirmed in another study performed in HIV-1–infected patients.18
In our study, we found that CD4+ T-cell count was not a covariate influencing the risk of CBI for patients with AHB. The median CD4+ T-cell count measured at the moment or close to when AHB occurred was higher than that found in the study by Bodsworth et al,14 which suggests that our group of patients had a more preserved immune status. In addition, a number of patients in our study were under DAART during AHB, whereas in Bodsworth et al.'s report, the patients were invariably untreated for HIV and HBV infection. Therefore, the different characteristics of patients may be responsible for this discrepancy in results.
Surprisingly, we found that an undetectable HIV-1 load during AHB seems to confer an increased risk of progression to CBI. Concerning the interaction between HBV and HIV at the replication level, hepatitis B has been shown to have minimal impact on HIV infection.20
Previous reports showed a transient increase in HIV-1 load during HBV vaccination21 or influenza virus vaccination.22 Such rebound of HIV load during standard vaccination can be attributed to activation of quiescent HIV-infected CD4+ T cells and, consequently, upregulation of HIV-1 replication.23 Although a quantitative HBsAg determination was not available during our study, the HBV-DNA levels did not differ between patients with RAHB and those who developed CBI. Therefore, an increased activation of quiescent CD4+ T cells in patients with RAHB compared with those who developed CBI would be unlikely.
Our finding could also be because patients with RAHB had a symptomatic HBV infection more frequently than those who developed CBI. However, we had no information from clinical records on hospitalization during AHB, which might have resulted in ART interruption, possibly justifying the difference in HIV load between these 2 groups. Nonetheless, the transaminase activity and bilirubin levels did not differ significantly between both groups, suggesting no substantial difference in the severity of AHB.
Our study also showed a marginal protective effect of DAART on the progression of AHB to CBI. A number of studies24–27 indicated a protective role of ART and DAART on the development of AHB in HIV-1–infected subjects. However, no data were provided in these studies on the clinical outcome of AHB after DAART exposure.
Recently, it has been shown that early initiation with lamivudine or entecavir in AHB seemed to reduce the likelihood of chronicity.28,29 Moreover, a network meta-analysis30 to assess the benefits of different pharmacological interventions for treating AHB concluded that there is currently no evidence of benefit of any intervention during AHB. However, HIV-1–positive patients were excluded from the analysis.
The rate of seroclearance for HBeAg (65.2%) in our study was greater than those found in previous studies6,16,31 performed in HIV-1–infected patients with CBI, but similar to that found in 1 study32 that showed 65% of HBeAg seroconversion in HIV-1–positive subjects with elevated ALT levels at baseline.
Notably, we obtained clinical and laboratory data for patients with progression of AHB to CBI, whereas previous studies investigated HIV-1–infected patients with stable CBI. Thus, it is possible that we measured the cumulative effect of 2 different events such as spontaneous and drug-induced HBeAg seroclearance.
For variables possibly associated with the loss of HBeAg in AHB that progressed to CBI, the CD8+ T-cell count and CD4+/CD8+ ratio were higher in patients who had HBeAg seroclearance than in those who maintained the HBeAg level during CBI.
AHB may cause an immune disturbance,33,34 and this effect is more evident in the components of CD8+ T cells, which are critical effectors in the control of AHB; however, as to why this dysregulation was less prominent in our patients who did not lose HBeAg remains to be elucidated.
This study has certain limitations due to the retrospective design of the study that need to be addressed. First, the serological markers of HBV infection were not evaluated at regular intervals, so it was difficult to determine the exact seroclearance for HBeAg and HBsAg in CBI. Second, the number of patients was small, and there were missing values for some baseline characteristics, which made it difficult for us to draw firm conclusions about the factors associated with CBI.
In conclusion, our findings suggest that initiating DAART early, possibly during AHB, might positively affect the course of AHB in HIV-1–infected patients. Furthermore, in individuals with CBI, long-term treatment with DAART could result in HBeAg and HBsAg seroclearance, which are valuable and optimal end points, respectively, in international guidelines.12
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