What this study adds: This case highlights the histopathological spectrum of dolutegravir-induced liver injury, documenting a rare granulomatous–cholangitic pattern. We aim to raise awareness of dolutegravir hepatotoxicity and caution against misclassification as infectious or autoimmune hepatitis. The case also underscores the diagnostic value of liver biopsy in atypical antiretroviral-associated liver injury.

Dolutegravir (DTG), a second-generation integrase inhibitor, is widely used in antiretroviral therapy because of its high efficacy, strong genetic barrier to resistance, and favourable safety profile.¹ Although generally well tolerated, DTG has been implicated in rare cases of drug-induced liver injury (DILI), which can result in acute liver failure and, in severe cases, liver transplantation.^1,2

The mechanisms underlying DTG-associated hepatotoxicity are incompletely understood, and may involve mitochondrial dysfunction, oxidative stress, and immune-mediated injury.² Histologically, reported cases most commonly demonstrate cholestatic or mixed patterns of liver injury, with limited biopsy-based descriptions of severe necrotic patterns.³ We report a rare and severe presentation of DTG-associated liver injury with unique histopathological features.

A 39-year-old woman living with HIV presented with a 7-day history of progressive jaundice associated with pruritus and intermittent retrosternal discomfort. She reported social alcohol consumption limited to weekends, totalling less than three units per week. Her past medical history was unremarkable, with no previous history of liver disease. She had been diagnosed 6 months previously with HIV and was initiated on a fixed dose combination of tenofovir-lamivudine-dolutegravir (TLD), with a CD4 count of 350 cells/μL and no current or previous opportunistic infections. A detailed medication and toxin exposure history was obtained, and there was no prior exposure to anti-tuberculosis therapy. She denied the use of over-the-counter (OTC) medications, traditional or herbal remedies, and weight-loss supplements. There was no reported recent exposure to industrial or environmental toxins. She was not receiving co-trimoxazole prophylaxis, isoniazid preventive therapy, or any other hepatotoxic medications.

On initial clinical assessment, she was severely jaundiced but haemodynamically stable, with no features of chronic liver disease or hepatic encephalopathy. Abdominal examination was unremarkable, with no hepatomegaly, ascites, or focal tenderness. An abdominal ultrasound demonstrated a liver of normal contour and morphology, with no focal hepatic lesions and no intrahepatic or extrahepatic bile duct dilatation. The gallbladder was distended and contained multiple gallstones, the largest measuring 18 mm × 7 mm, with gallbladder wall thickening of 4 mm and no pericholecystic fluid. The common bile duct measured 3 mm, with no choledocholithiasis identified.

Liver function testing demonstrated severe hepatic dysfunction with a marked cholestatic–hepatocellular pattern, including marked hyperbilirubinaemia, severe transaminitis, and an elevated International Normalised Ratio (INR) of 1.47 at presentation. Hepatitis A, B, and C serology was negative, and other baseline investigations were unremarkable (Table 1 to Table 4). A magnetic resonance cholangiopancreatography (MRCP) was performed and showed no dilatation of the intrahepatic or extrahepatic biliary tree and no obstructing calculi. The gallbladder wall appeared thickened and oedematous, with multiple small calculi. Furthermore, no focal liver lesions, contour abnormalities, or hepatomegaly were identified.

Following withdrawal of TLD, the patient demonstrated substantial biochemical improvement with downtrending bilirubin and transaminase levels with progressive normalisation of the INR during admission. However, there was a transient secondary rise in transaminases and cholestatic enzymes, particularly gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP), despite an overall improving biochemical trajectory (Table 2). This prompted initiation of corticosteroid therapy, namely oral prednisone, at a dose of 20 mg in the context of worsening transaminase levels, elevated immunoglobulin G, and a weakly positive autoimmune screen, raising concern for an immune-mediated process. Corticosteroids were subsequently tapered. As corticosteroid therapy had already been initiated prior to liver biopsy, the degree of inflammatory activity on histology may have been partially modified by treatment, a consideration that was taken into account when interpreting the biopsy findings. In view of the persistent and unexplained liver injury despite initial medical management, a decision was made to proceed with liver biopsy.

Liver core biopsy demonstrated preserved lobular architecture with extensive subacute hepatic necrosis and reticulin collapse (Figure 1). Portal tracts were expanded by a mixed inflammatory infiltrate comprising lymphocytes, plasma cells, neutrophils, histiocytes, eosinophils, and numerous non-necrotising granulomas composed of epithelioid histiocytes and multinucleated giant cells, occasionally surrounding small bile ducts. Bile duct epithelial injury and ductular proliferation were present, with mild interface activity. Notably, there was no prominent plasma cell clustering or significant plasma cell participation in the interface activity. Special stains were negative for acid-fast bacilli and fungi. In addition, mycobacterial tuberculosis polymerase chain reaction performed on liver tissue was negative, and liver tissue culture for Mycobacterium tuberculosis showed no growth. Overall, the findings were most consistent with a granulomatous–cholangitic pattern of DILI, likely associated with DTG.

She was followed up at 1 month and at 4 months, during which she demonstrated progressive clinical and biochemical improvement. She had resolution of jaundice and pruritus with a significant improvement, though not complete normalisation, of her liver function tests (Table 2). In the context of suspected DTG-associated DILI, the patient was switched to a non-DTG-containing antiretroviral regimen consisting of lopinavir/ritonavir (LPV/r) and rilpivirine (RPV). HIV care remained uninterrupted following this change, with stable CD4 counts and sustained virological suppression.

DTG-associated hepatotoxicity is uncommon, and is most frequently described as mild, transient liver enzyme elevation, typically manifesting as cholestatic or mixed hepatocellular–cholestatic injury.² While liver enzyme abnormalities have been reported in patients receiving DTG-based regimens, clinically significant DILI remains rare, and progression to severe hepatic failure has been documented only in isolated case reports.³ Importantly, despite extensive global use of DTG, biopsy-proven cases of severe DTG-associated DILI are rare, with most published literature relying on clinical and biochemical criteria rather than histological confirmation.^2,4 Consequently, the histopathological spectrum of DTG-induced liver injury remains poorly characterised.

The most striking feature of this case was a granulomatous–cholangitic pattern of liver injury, characterised by extensive subacute zonal and bridging necrosis, numerous portal-based non-necrotising granulomas, and bile duct epithelial injury with ductular proliferation. While severe necrosis may be seen in immune-mediated or toxic injury, granulomatous inflammation with a cholangitic component is not a recognised dominant pattern in reported cases of DTG-associated hepatotoxicity, underscoring the atypical nature of this presentation.

Notably, despite marked biochemical improvement following DTG withdrawal, our patient demonstrated a transient secondary rise in transaminases and cholestatic enzymes prior to eventual recovery. This biphasic pattern has been described in cholangitic forms of DILI, and may reflect delayed resolution of bile duct epithelial injury despite improvement in the initial hepatocellular insult.⁵ Cholestatic DILI is recognised to resolve more slowly than hepatocellular injury, and may demonstrate fluctuating biochemical abnormalities during recovery because of ongoing ductular inflammation and cholangiocyte injury.^5,6 Additionally, the granulomatous–cholangitic histological pattern in our case supports a possible immune-mediated mechanism, whereby hepatic inflammation may transiently persist, even after withdrawal of the offending agent.^5,6

Accordingly, granulomatous hepatitis in individuals living with HIV presents a broad differential diagnosis, including infectious causes such as tuberculosis and fungal disease, immune-mediated conditions such as sarcoidosis or autoimmune hepatitis, and DILI.⁷ In this case, infectious aetiologies were considered unlikely given the absence of necrotising granulomas, negative special stains for acid-fast bacilli and fungi, and lack of ancillary clinical or radiological features suggestive of disseminated tuberculosis or other infections.

Autoimmune hepatitis (AIH) was therefore considered in view of the patient’s gender, antinuclear antibody (ANA) positivity (1:80), and elevated IgG level (22.4 g/L). Using the 2008 Simplified International Autoimmune Hepatitis Group (IAIHG) criteria,⁸ she accrued 2 points for ANA positivity, 2 points for elevated IgG (> 1.1 × upper limit of normal), and 2 points for exclusion of viral hepatitis, with histology considered at most ‘compatible’ (1 point), yielding a cumulative score of 6–7, which approaches the threshold for probable AIH (≥ 6). However, the biopsy lacked typical features of AIH and instead demonstrated granulomatous inflammation, which is distinctly uncommon in this condition. Furthermore, recent International AIH Pathology Group (IAIHPG) consensus recommendations emphasise injury topography and portal-based plasma cell-rich inflammation as key diagnostic features,⁹ which were absent in this case.

Although the simplified score approached the threshold for probable AIH, the absence of typical histological features, and a relevant drug exposure history, are incompatible with classification as likely AIH under established diagnostic frameworks. Additionally, elevated IgG and ANA positivity may reflect non-specific immune activation in the context of HIV infection rather than true autoimmune hepatitis.⁹ Taken together, the overall clinicopathological picture was most suggestive of a DTG-associated DILI, although the atypical granulomatous–cholangitic pattern and overlapping immune-mediated features warrant cautious interpretation. Using the Roussel Uclaf Causality Assessment Method (RUCAM),¹⁰ the patient achieved a score of 6, consistent with probable DILI. DTG was considered the most likely causative agent in the absence of alternative toxin exposure or concomitant hepatotoxic medications.

In this case, liver biopsy was essential after non-invasive investigations failed to establish a unifying diagnosis, providing definitive evidence of a granulomatous–cholangitic pattern with subacute necrosis, and allowing exclusion of infectious and primary autoimmune causes. This case highlights that DTG-associated hepatotoxicity may present with granulomatous and cholangitic features, broadening the diagnostic framework for unexplained liver injury in individuals living with HIV, and underscoring the value of liver biopsy in complex presentations.