Case Report: Successful treatment with Dolutegravir containing antiretroviral therapy for acute on chronic liver failure by HBV in patients with HIV infection

doi:10.21203/rs.3.rs-1755191/v1

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Case Report

Case Report: Successful treatment with Dolutegravir containing antiretroviral therapy for acute on chronic liver failure by HBV in patients with HIV infection

https://doi.org/10.21203/rs.3.rs-1755191/v1

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Background: There’s no clear antiretroviral treatment for HIV/HBV co-infected patients with acute-on-chronic liver failure (ACLF) because of the vast majority of antiretroviral medications have hepatotoxicity. In this case report, we described two HIV/HBV co-infected ACLF patients treated with HAART regimen containing Dolutegravir (DTG) and successfully achieved symptom relief and viral suppression.

Results: Two cases of HIV/HBV coinfection with ACLF who attempted to receive HAART containing DTG and were successfully treated without liver damage, immune reconstitution inflammatory syndrome (IRIS) or other complications occurred.

Conclusions: It is proved that the application of DTG in HIV/HBV co-infected patients with ACLF has certain safety, which provides certain clinical basis for future prospective studies.

HIV

HCV

coinfection

ACLF

Dolutegravir

It is estimated that about 10% of human immunodeficiency virus (HIV) infected patients in China are chronically infected with hepatitis B virus (HBV). The incidence and mortality of liver-related diseases in HIV/HBV co-infected patients were higher than those in patients infected with HBV alone. Therefore, current guidelines suggest that HIV/HBV co-infected patients without special contraindications should receive highly active antiretroviral therapy (HAART) which is against HBV either as soon as possible. However, it is not applicable for HIV/HBV co-infected patients with acute-on-chronic liver failure (ACLF) because of the vast majority of antiretroviral medications have some degree of hepatotoxicity. There are few reports on the treatment of HIV/HBV co-infected patients with ACLF, and there is still a lack of recommended therapy for such patients. We describe two cases of HIV/HBV co-infected patients with ACLF successfully treated with HAART regimen containing Dolutegravir (DTG).

Patient A

A 51-year-old Chinese male presented with right abdominal herpes, abdominal distension and edema of both lower extremities for 3 weeks. He was chronic HBV infection without any anti-HBV treatment and had the history of high-risk sexual behavior. The ultrasonography of the abdomen in local hospital suggested prompt diffuse liver damage which considered as liver cirrhosis with ascites and was transferred to Tangdu hospital because of HIV antibody positive.

Physical examination was remarkable for jaundice of skin and sclera, scattered white spots in oral cavity, positive liver-palms, spider-burst in head and neck, abdominal bulge, mobile voiced positive and severe edema of lower limbs. Blood investigations revealed WBC 12.06×10⁹/L, PLT 57×10⁹/L, AFP 85.50ng/ml, hypoproteinemia(ALB 19.8g/L), raised serum liver enzymes(ALT 65U/L, AST 76U/L), high bilirubinemia(TBIL 80.80µmol/L, DBIL 50.41µmol/L, IBIL 30.41µmol/L), normal renal function(BUN 11.91mmol/L, Cr 69.52umol/L), aberrant coagulation(PTA 37.8%, INR 1.70) and acute inflammatory state(PCT 0.70ng/ml, CRP 30.13mg/L). Serologic screening showed HBsAg 694.54 IU/mL, HBeAg 198.40 COI, Anti-HBc 138.70 COI, HBV DNA 6.66×10⁶IU/mL while antibodies against Hepatitis A, Hepatitis C, Hepatitis D and Hepatitis E viruses were negative. Screening for HIV antigens and antibodies were positive and HIV RNA in plasma was 5.71×10³ copies/mL. Peripheral blood CD4⁺ T-cells were 111/µl while ultrasonography of the abdomen revealed diffuse liver lesions, widened portal vein, and less-moderate ascites.

He was thus diagnosed with acquired immunodeficiency syndrome (AIDS), hepatitis B cirrhosis and ACLF with Child-Pugh C. We formulated an HAART treatment plan for the patient on the 4th day after admission, which consisted of DTG 50mg plus Lamivudine (3TC) 300mg plus Tenofovir (TDF) 300 mg once daily. Anti-infection therapy, diuretic treatment, liver-protective and symptomatic treatments were used to improve clinical symptoms. We repeatedly infused frozen plasma to him during hospitalization and dynamically monitored his blood routine, functions of liver, kidney and coagulation (Fig. 1). On day twenty-one after admission, his abdominal distension was relieved, ascites subsided and edema of lower limbs subsided. Laboratory examinations showed that his liver and kidney function was basically normal. HBV DNA reduced to 8.23×10⁴IU/mL and HIV RNA reduced to 23 copies/mL.

Patient B

A 46-year-old Chinese male presented with fatigue, jaundice of skin and sclera for 2 weeks. His past medical history was unrevealing except for sex with other men. Laboratory examinations in local hospital revealed abnormal liver function and coagulation (ALT 629U/L, AST 521U/L, TBIL 255umol/L, DBIL 132umol/L, ALB25.1g /L and PTA 28.0%). Abdominal ultrasonography showed that the liver light spot increased and the spleen slightly enlarged. His HBsAg, Anti-HBe, Anti-HBc were positive and has taken entecavir (ETV) to against HBV. He was finally transferred to Tangdu hospital because of HIV antibody positive.

Physical examination was remarkable for jaundice of skin and sclera, positive liver-palms, abdominal bulge, mobile voiced positive and perineum swelling. Laboratory tests revealed WBC 12.00×10⁹/L, PLT 55×10⁹/L, AFP 69.00ng/ml, hypoproteinemia(ALB 30.3g/L), raised serum liver enzymes(ALT 138U/L, AST 104U/L), high bilirubinemia(TBIL 192.48µmol/L, DBIL 136.85µmol/L, IBIL 55.63µmol/L), normal renal function(BUN 4.05mmol/L, Cr 82.21umol/L), aberrant coagulation(PTA 26.5%, INR 2.16) and acute inflammatory state(PCT 1.35ng/ml, CRP 14.37mg/L). Serologic screening showed Anti-HBe 100.01 COI, Anti-HBc 547.20 COI, HBV DNA 5.21×10³IU/mL while antibodies against Hepatitis A, Hepatitis C, Hepatitis D and Hepatitis E viruses were negative. Screening for HIV RNA in plasma was 4.35×10⁴copies/mL. Peripheral blood CD4⁺ T-cells were 56/µl and CD8⁺ T-cells were 1780/µl. Abdominal ultrasonography revealed cirrhosis with a small amount of ascites while perineal ultrasonography showed subcutaneous abscess formation (1.0 cm × 1.5 cm × 3.4 cm).

He was thus diagnosed with acquired immunodeficiency syndrome (AIDS), hepatitis B cirrhosis, perineal abscess and ACLF with Child-Pugh C. We formulated an HAART treatment plan and suspended ETV for the patient on the 3rd day after admission, which consisted of DTG 50mg plus 3TC 300mg plus TDF 300 mg once daily. Anti-infection therapy, jaundice-relieving, liver-protective and symptomatic treatments were used to improve clinical symptoms. Perineal abscess puncture drainage was performed on day ten after admission while the pus was cultured with Enterobacter aerogenes and Enterococcus faecalis positive. We repeatedly infused frozen plasma, artificial liver blood purification (dual plasma molecular adsorption system + plasma exchange, DPMAS + PE) to him during hospitalization and dynamically monitored his blood routine, functions of liver, kidney and coagulation (Fig. 2). On day twenty-four after admission, his abdominal distension and ascites were relieved. Laboratory examinations showed that his liver, kidney and coagulation function was basically normal. On day 286 after HAART, his serologic screening showed HBV DNA was lower than 20IU/mL and HIV RNA was 37copies/mL, while peripheral blood CD4⁺ T-cells were 167/µl and CD8⁺ T-cells were 937/µl.

By the end of 2021, there were about 1.142 million HIV-1 infected patients with 111,000 newly infections in China [1]. HIV and HBV have similar route of transmission in clinic and approximately 10% of HIV infected patients in China are chronically coinfected with HBV [2]. HIV/HBV co-infection can accelerate the immune damage process of HIV/AIDS, aggravate the degree of liver inflammation damage and destruction of CD4 + T lymphocyte, promote liver inflammation necrosis and fibrosis, increase the risk of liver toxicity of drugs and resulting in significantly higher incidence of severe clinical outcomes and liver-related mortality than patients infected with either virus alone [3–5]. ACLF is defined as acute liver injury characterized by jaundice, coagulation dysfunction (serum TBil ≥ 85 µmol/L, PTA ≤ 40% or INR ≥ 1.5), ascites and/or hepatic encephalopathy within 1 month in patients with chronic liver disease or cirrhosis. According to the basis of different chronic liver diseases, ACLF was divided into three types: Type A is based on chronic non-cirrhotic liver disease, Type B is based on compensated cirrhosis and Type C is based on decompensated cirrhosis [6, 7]. There are many incentives for ACLF while the HBV infection is the main incentive in China, and ACLF is often seen in HIV/HBV co-infected patients.

Numerous previous studies have shown that the disease status, progression and regression of ACLF patients are closely correlated with the patients' autoimmune level and mechanism of injury [8–10]. The levels of inflammatory factors such as leukocytes, plasma CRP, TNF-α, IL-6 and IL-8 were significantly higher in patients with ACLF than in those without ACLF, while the levels of leukocytes and plasma CRP correlated with the severity of the disease in patients with ACLF. Pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines can activate macrophages in the liver microenvironment and initiate natural immunity during inflammatory activity in ACLF patients, which causing immune damage to the liver [11]. The composition ratio of peripheral blood Th17 cells was significantly higher in patients with HBV-ACLF than in patients with chronic HBV and healthy controls, which was positively correlated with serum ALT levels and liver tissue inflammatory activity [12]. Meanwhile, the proportion of HBV-specific cytotoxic T lymphocytes and activated CD8 + T lymphocytes in peripheral blood and liver tissue is significantly increased in ACLF patients [13]. A clinical study in China showed that patients with HIV/HBV-ACLF had lower ALT, ALB, Hb and PLT than patients with HBV-ACLF alone, but higher HBV DNA levels, which may be due to HIV co-infection resulting in impaired immune function, poorer disease status, lower degree of liver inflammatory response and weaker ability to clear HBV[14]. In conclusion, the production of ACLF has an important correlation with the natural and acquired immunity, while patients with HIV/HBV-ACLF will face more complex clinical problems and severe clinical regression due to the continuous influence of both viruses in the body and the disruption of immune function.

There are recommended antiviral therapy for HIV/HBV co-infection in both domestic and international guidelines currently, but there are no clear recommendations for patients with ACLF. At present, it is believed that HIV/HBV co-infected people regardless of CD4 + T lymphocyte counts, as long as there is no indication for anti-HIV delayed treatment, it is recommended to start HAART programs which simultaneously against the HIV and HBV. Two kinds of nucleoside drugs with anti-HBV activity must be included to avoid the use of single drug which may induce HIV resistance. TAF/TDF plus 3TC/FTC can be considered as the backbone part of the HAART regimen, while the third kind of drugs include non-nucleoside reverse transcriptase inhibitors (NNRTIs such as EFV, RPV), protease inhibitors (PIs such as LPV/c, DRV/c) or integrase strand transfer inhibitors (INSTIs such as DTG, RAL). ETV cannot be considered part of the HAART regimen because of its weak anti-HIV activity [15, 16]. However, because most NNRTIs and PIs are hepatotoxic and can aggravate liver damage, they are contraindicated for use in ACLF. Previous clinical studies have shown that INSTIs can be used in patients with Child-Pugh A and B. However, there are no published safety data on the use of INSTIs in ACLF patients with severely impaired liver function [17]. The usage of RAL + TDF + FTC as the regimen of HBV/HIV-acute liver failure patient has also been reported in the literature, but the patient eventually died due to overwhelming disease [18].

Both HIV/HBV co-infected patients in our case report met the diagnostic criteria for ACLF. Both patients had clear manifestations of chronic HBV infection with severe hepatic impairment and ascites prior to initiation of ART. Anti-infection therapy, plasma infusion, jaundice-relieving, diuretic, liver-protective and symptomatic treatments were immediately used to improve their clinical symptoms after admission. Considering the patient with Child-Pugh C, we used the HAART regimen of DTG + TDF + 3TC and closely monitored their liver function and coagulation function. Both patients showed gradual improvement in liver function and coagulation function after treatment. Post-discharge follow-up also showed no further deterioration of liver function in either patient, suggesting that the HAART regimen including DTG may be effective for HBV/HIV co-infected patients with cirrhotic decompensation or ACLF, which may help avoid liver transplantation. However, severe liver damage has also been reported in HBV/HIV co-infected patients with Child-Pugh A using HAART regimens containing DTG, which may be related to IRIS-induced liver inflammatory damage [19, 20]. Therefore, the use of HAART regimens containing INSTIs such as DTG in patients with ACLF still requires close monitoring of liver function.

In conclusion, for these two patients with HIV/HBV-ACLF, the attempted HAART treatment consist of DTG + TDF + 3TC was effective and did not result in serious liver damage, IRIS or other complications, which demonstrating the safety of DTG in patients with ACLF and Child-Pugh C. However, the clinical use of INSTIs is still in the exploratory stage because there are no relevant studies on the level of pharmacokinetics and safety of INSTIs in such patients. Although there are only two cases, our report suggests that patients with HIV/HBV-ACLF can be treated experimentally with INSTIs and provides some clinical basis for future relevant prospective studies.

ACLF acute-on-chronic liver failure

AIDS acquired immunodeficiency syndrome

DAMPs damage-associated molecular patterns

DPMAS dual plasma molecular adsorption system

DTG Dolutegravir

HARRT highly active antiretroviral therapy

HBV hepatitis B virus

HIV human immunodeficiency virus

INSTIs integrase strand transfer inhibitors

NNRTIs non-nucleoside reverse transcriptase inhibitors

PAMPs Pathogen-associated molecular patterns

PE plasma exchange

PIs protease inhibitors

TDF Tenofovir

3TC Lamivudine

Ethics approval and consent to participate

This case report was approved by the Ethics Committee of the Second Affiliated Hospital of Air Force Military Medical University, and data of patients were used for scientific research purposes only.

Consent for publication

We have obtained the consent for publication from all patients.

Availability of data and materials

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author

Competing interests

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding:

This work is funded by the National Science and Technology Major Project during the 13th Five-Year Plan Period (2017ZX10202101-003-007, 2017ZX10202101-004-005, 2017ZX10202203-008-003, 2017ZX10202102-002-001), Air Force Logistics Key Funding Program（BKJ20J001）

Authors’ contributions

Mingyuan Bi, Yushen Liu, Wenzhen Kang and Yongtao Sun managed and treated patients. Mingyuan Bi mainly wrote the manuscript. As the corresponding author, Wen Kang carefully checked the whole manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

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Case Report: Successful treatment with Dolutegravir containing antiretroviral therapy for acute on chronic liver failure by HBV in patients with HIV infection

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Abstract

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Case Presentation

Patient A

Patient B

Discussion And Conclusions

Abbreviations

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