key: cord-1018696-jqe81gwf authors: Rodríguez‐Tajes, Sergio; Miralpeix, Anna; Costa, Josep; López‐Suñé, Ester; Laguno, Montserrat; Pocurull, Anna; Lens, Sabela; Mariño, Zoe; Forns, Xavier title: Low risk of hepatitis b reactivation in patients with severe COVID‐19 who receive immunosuppressive therapy date: 2020-09-24 journal: J Viral Hepat DOI: 10.1111/jvh.13410 sha: 6959c694a8120879547c4f077a985341529c2389 doc_id: 1018696 cord_uid: jqe81gwf A significant proportion of patients infected with SARS‐CoV‐2 develop severe respiratory symptoms due to an excessive immune response. Treatment of this condition may include immunosuppressive therapies, such as IL‐6 receptor antagonists and corticosteroids, which poses a risk for patients with active or past hepatitis B virus (HBV) infection. In this prospective cohort study we analyzed the risk of HBV reactivation in patients with severe COVID‐19 and resolved HBV infection undergoing immunosuppressive therapy. From March 15(th)to April 30(th)2020, 600 patients with severe COVID‐19 were admitted into our Hospital and treated with immune‐modulators. Data regarding HBV infection was available in 484, of whom 69 (14%) were HBsAg negative/anti‐HBc positive. For these patients, HBV reactivation prophylaxis with entecavir was strongly recommended. Complete follow‐up was available in 61 patients: 72% were male, median age was 67 years, and anti‐HBs was >10 IU/mL in 72%. The immunosuppressive drug most used was tocilizumab (72%). Despite HBV prophylaxis recommendation, 38 (62%) patients received entecavir and 23 (38%) did not. Baseline features of both groups were similar. At follow‐up, we found no cases of HBsAg seroreversion and only 2 (3%) patients (no prophylaxis group) had detectable serum HBV‐DNA (<15 IU/mL). Both were anti‐HBs negative and had normal aminotransferase levels. Our data show that the risk of HBV reactivation in patients with severe COVID‐19 and resolved HBV infection undergoing immunosuppressive treatment is low. However, if a systematic follow‐up after hospital discharge is unfeasible in patients without anti‐HBs, a short course of antiviral prophylaxis may be a safe option. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing a pandemic with more than 7 million infections worldwide and 400,000 fatalities so far. COVID-19 (the disease caused by SARS-CoV-2) is usually mild, but around 20% of infected individuals develop severe respiratory symptoms that require hospitalization and, in some cases, intensive care support (1, 2) . Although the pathogenesis of SARS-CoV-2 infection is not yet completely understood, in some patients there is an excessive immune response to the virus, known as a "cytokine storm". The latter mediates severe lung inflammation and for this reason, patients are treated with immunosuppressive therapies aimed at limiting immune mediated damage (3) . Corticosteroids, IL-6 and IL-1 receptor antagonists, as well as janus kinase inhibitors are some of the drugs that have been used in patients with severe COVID-19. The use of these drugs may pose a risk for patients with active or past hepatitis B virus (HBV) infection. Hepatitis B reactivation associated with immune suppressive and biological therapies is an important cause of morbidity and mortality in patients with current or past exposure to HBV (4) . In HBsAg-positive patients, HBV reactivation is defined as a sudden and rapid increase in HBV-DNA levels in patients with previously detectable DNA or reappearance of HBV-DNA viremia in individuals who did not have viremia before the initiation of immune suppressive therapy (5) . In individuals who are initially negative for HBsAg and anti-HBc positive, HBV reactivation is defined by appearance of HBsAg and/or HBV-DNA. Following HBV reactivation, ALT elevation can occur and, in some cases, this can evolve into a fulminant hepatic failure. The risk of HBV reactivation is highly dependent on the status of HBV infection, as well as on the type of immune suppressive therapy. The highest risk of reactivation occurs in patients with active or past HBV infection treated with B-cell-depleting agents such as rituximab, and in HBsAg positive patients who receive high-dose corticosteroids, anthracyclines or potent TNF-alfa inhibitors (5) (6) (7) . Except for high-dose corticosteroids, all the immune modulators used to treat cases of severe COVID-19 are considered of low risk, particularly in HBsAg negative anti-HBc positive patients. This article is protected by copyright. All rights reserved Since past HBV infection is a relatively common condition (≈10%) (8) , our aim was to assess the risk of HBV reactivation and the utility of nucleoside analog (NUC) prophylaxis in HBsAg negative/anti-HBc positive patients who were admitted to the hospital for severe and underwent immune suppressive therapy. This is a prospective cohort study conducted in a single center (Hospital Clínic of Barcelona). All patients admitted to our center from March 15 th to April 30 th 2020 with a diagnosis of COVID-19 who had an indication for immune modulatory therapy were tested for markers of present (HBsAg) or past (anti-HBc) hepatitis B virus infection. HBsAg or anti-HBc positive patients were included in the study. The following drugs were considered as immunosuppressive therapy: 1) interleukin-6 receptor antagonists (tocilizumab, siltuximab); 2) interleukin-1 receptor antagonists (anakinra); 3) janus kinase inhibitors (baricitinib) and 4) high-dose corticosteroids. Tocilizumab was administered in a single dose of 400 mg (600 mg if weight > 75 Kg); some patients received a second dose within the next 24 hours if there was an unfavorable clinical course. Siltuximab was administered as a single dose of 800 mg. Anakinra was administered at a dose of 200 mg/12h the first day and 200mg/day the following 2 days. Baricitinib was administered at a dose of 4 mg/d for 3 days. Regarding corticosteroid therapy, methylprednisolone was dosed at 250 mg/d for 3 days, followed by 30 mg/d for a week. In patients with suspected organizing pneumonia, treatment with prednisone 0.5 mg/kg/day was initiated and extended for at least one month. Due to the complex and rapidly evolving situation during the pandemic's peak, the immunosuppressive treatment regimen was decided according to the physicians' criteria, availability of drugs at the time of admission, or based on inclusion in ongoing clinical trials. This article is protected by copyright. All rights reserved The study was approved by the Hospital Ethics Committee. All patients gave oral consent to participate in the study. Once patients were discharged from the center, a written informed consent form was provided to all patients in order to obtain their signature. From March 15 th to April 30 th 2020 600 patients with severe COVID-19 were admitted into our Hospital and were treated with an immune modulator. Data of HBV infection status was available in 490 (81%) patients, 3 of whom (0.6%) were HBsAg positive and 69 (14%) were HBsAg negative/anti-HBc positive (Fig 1) . As expected in our geographical area, the prevalence of anti-HBc increased with age and was higher than 15% in individuals over 60 years ( Supplementary Fig 1) . This article is protected by copyright. All rights reserved Table 1 : 72% were men, median age 67 (59-75) years, the most frequent comorbidities were arterial hypertension (62%), diabetes mellitus (36%) and dyslipidemia (33%). Fifty-three (87%) patients had abnormal (Table 1) . Thirty-eight (62%) patients received entecavir prophylaxis and 23 (38%) did not (Fig 1) . Although the hospital protocol recommended NUC prophylaxis for anti-HBc positive patients undergoing immune modulator treatments, the decision to indicate HBV prophylaxis depended on the treating physician. As shown in Table 1 , relevant baseline features of both groups (prophylaxis/ no prophylaxis) were similar regarding age, gender, presence of comorbidities, immune modulator regimen and laboratory tests. After being discharged, 19 (31%) patients were transferred to a nursing home or rehabilitation center for continuing their recovery; the proportion was similar in patients who did or did not receive entecavir prophylaxis. Follow-up data after hospital discharge was available in 57 (93%) of the 61 patients (4 patients were lost after discharge). Among these 57 patients we did not identify a single case of HBsAg seroreversion (positive HBsAg), and we only detected 2 cases of positive HBV-DNA. In both, HBV viral load was below the quantification limit (< 15 IU/mL). None of these 2 patients had undergone entecavir prophylaxis and both were negative for anti-HBs. One case (male, 77 years old) had received siltuximab and methylprednisolone 250 mg/d (3 days) followed by prednisone 0.5 mg/kg due to suspected organizing pneumonia, whereas the second case (male, 64 years old) was treated with a single dose of tocilizumab. This article is protected by copyright. All rights reserved Concerning aminotransferase elevations, the proportion of patients with abnormal ALT levels (above the ULN) decreased from 87% (peak during hospitalization) to only 35% at follow-up (4% with ALT values 3 times above ULN). ALT values were within the normal range in the 2 individuals with detectable HBV-DNA. Regarding the 3 HBsAg positive patients, 2 had positive HBV-DNA (10 9 IU/mL and 15 UI/mL, respectively) whereas one patient (who was coinfected with HIV undergoing tenofovir therapy) had undetectable HBV-DNA. Entecavir prophylaxis was initiated in the 2 patients with positive HBV-DNA and they are currently followed at our liver clinic. The results of our study show that a short course of immune modulator therapy does not appear to increase the risk of HBV reactivation in patients with severe COVID-19 with markers of past HBV infection. Drugs used to treat the disproportionate immune response after SARS-Cov-2 infection (mainly IL-6 receptor antagonists or high dose corticosteroids) are considered of moderate risk for HBV reactivation in HBsAg negative/anti-HBc positive individuals (5) (6) . Nevertheless, we decided to recommend NUC prophylaxis for several reasons. First, a significant proportion of patients admitted to the hospital with severe COVID-19 are old males with significant comorbidities, which are considered risk factors for HBV reactivation. Second, SARS-Cov-2 infection induces significant lymphopenia, which might increase the possibility of HBV reactivation. Finally, due to the extremely high burden of the pandemics on our health care system, we could not guarantee a proper follow-up after patient discharge from the hospital, particularly older patients who returned to a nursing home. The latter is highly recommended for patients at risk of HBV reactivation if no prophylaxis is indicated. Despite the strong recommendation to include HBV prophylaxis in patients undergoing immune suppressive treatment, not all treating physicians indicated entecavir. The latter allowed us to compare outcomes of individuals with and without HBV prophylaxis. The main baseline features of both groups were comparable and we only detected positive HBV-DNA in 2 patients who had not received entecavir prophylaxis. The two cases were anti-HBs This article is protected by copyright. All rights reserved negative. In both cases, HBV-DNA remained below the limit of quantification and was not accompanied by ALT elevations. Our data regarding the low risk of HBV reactivation using IL-6 receptor antagonists is supported by some reports in patients with rheumatoid arthritis (9) (10) . In a recent study, which included 152 patients with resolved HBV infection treated with disease-modifying anti-rheumatic drugs (25 with tocilizumab), the risk of HBV reactivation was very low (< 5%) (10) . Nevertheless, patients who were anti-HBs negative showed a significantly higher incidence of HBV reactivation (15%), as already reported in other studies (11) . Reactivation, defined as detectable HBV-DNA at any point during therapy, tended to occur several months after immunosuppressive treatment initiation (in contrast with the short course therapy in our scenario). In cases where HBV-DNA did not rise above the limit of quantification, antiviral treatment was not indicated and the final outcome was excellent (12) . A completely different scenario applies to patients with active infection (HBsAg positive), in whom cases of reactivation and even fulminant hepatic failure have been reported during tocilizumab therapy (13) . Regarding the high prevalence of abnormal aminotransferases, our results are consistent with other articles were the liver impairment has been reported in up to 75 % in patients with severe COVID-19 (14) . The mechanism of liver damage during COVID-19 is not fully understood but it seems related, at least in part, with the highly activated inflammatory status (15) (though it can be influenced by multiple additional factors, as drug toxicity). The elevation of aminotransferases is usually mild and transient (16) , as seen in our patients. Our study has several limitations. First, the small sample size, which does not allow to draw definitive conclusions. Second, the fact that this was not a randomized study: the decision to indicate NUC prophylaxis in HBsAg negative anti-HBc positive patients depended on the treating physician, although we did not find significant differences between treated and untreated patients. Third, the duration of NUC prophylaxis is arguable. We based our decision on the fact that most patients received a single dose of immune modulator. Moreover, except for patients with suspected organizing pneumonia, duration of corticosteroid treatment did not overcome one month. In addition, due to characteristics of Accepted Article patients with severe COVID-19 (old age, comorbidities, residency at nursing homes), we chose to minimize pill burden and medical interventions. In summary, our data show that the risk of HBV reactivation in patients with severe CODIV 19 and resolved HBV infection undergoing immune modulator treatment is low. Follow-up after patient discharge is recommended, but if this is not possible due to the burden of the pandemic, a short course of antiviral prophylaxis may be a safe alternative in patients without anti-HBs. 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High dose steroids were administered in combination with other immune modulators (20) or given as monotherapy (5) .