Didanosine and Liver Toxicity: 2025 Guide to Risks, Symptoms, and Monitoring

Didanosine changed HIV care in the 1990s, but it also carries a real risk to the liver-ranging from simple enzyme bumps to dangerous lactic acidosis and a rare condition called noncirrhotic portal hypertension. If you’re on it, used it in the past, or you’re reviewing a patient’s old regimen, you want straight answers: What’s the risk, who’s most vulnerable, and how do you stay safe? That’s what we’ll map out here. I’ll keep it practical and evidence-backed so you can act with confidence.

TL;DR

• Didanosine is rarely used in 2025, but liver injury can still occur-especially with long-term use, combination with stavudine or ribavirin, and in people with hepatitis B/C.
• Main patterns: enzyme elevations, mitochondrial toxicity (fatty liver and lactic acidosis), and noncirrhotic portal hypertension (due to nodular regenerative hyperplasia).
• Higher risk: female sex, obesity, pregnancy, alcohol use, pre-existing liver disease, and drug interactions (allopurinol, ribavirin, tenofovir, hydroxyurea).
• Typical clinic rules: stop or switch if ALT/AST >5× ULN without symptoms, or >3× ULN with symptoms, or bilirubin >2× ULN, or any signs of lactic acidosis. Call urgently for jaundice, severe abdominal pain, deep/rapid breathing, or confusion.
• Modern guidelines (DHHS 2024; BHIVA 2023; WHO 2022) recommend alternatives in most cases. Always coordinate changes with an HIV specialist.

What didanosine does to the liver and why it happens

Didanosine (ddI, brand once known as Videx) is an older nucleoside reverse transcriptase inhibitor (NRTI). It helped suppress HIV at a time when options were limited, but its toxicity profile is tough. In 2025, most high-income settings have retired it from routine use. Still, people may be on legacy regimens, and past exposure can leave a footprint, especially in the portal circulation of the liver.

Three main liver injury patterns show up with didanosine:

• Transaminase elevations: Mild to moderate bumps in ALT/AST are not rare. Many are transient, but they can herald something deeper, especially with other stressors like hepatitis B or C.
• Mitochondrial toxicity: Didanosine inhibits mitochondrial DNA polymerase-γ. That can lead to microvesicular steatosis (fatty change) and, in severe cases, lactic acidosis with hepatomegaly-events that can be life-threatening. Risk jumps with stavudine and ribavirin.
• Noncirrhotic portal hypertension (NCPH): A longer-term, insidious problem linked to nodular regenerative hyperplasia (NRH). The liver may look firm but not scarred like classic cirrhosis. People present with splenomegaly, low platelets, varices, or GI bleeding, sometimes after years on didanosine.

How common is this? Numbers vary by population and era. Transaminase elevations have been reported in about 2-10% of users in older cohorts. Pancreatitis-another signature didanosine toxicity-shows up in roughly 1-9% depending on dose, duration, and co-medications. Clinically significant lactic acidosis is uncommon but serious, with higher rates in didanosine-stavudine combinations and in pregnancy. NRH/NCPH remains rare but well documented after prolonged exposure. These patterns are detailed by LiverTox (NIH), FDA/EMA product information, and HIV treatment guidelines.

Timing matters. Mitochondrial toxicity and lactic acidosis can emerge within weeks to months, often earlier when combined with stavudine or ribavirin. NCPH tends to appear after long-term use-often several years in. Transaminase elevations can occur at any time, but watch the first 3-6 months and any period of medication changes or intercurrent illness.

What does this look like in real life?

• Mitochondrial pattern: fatigue, nausea, abdominal pain, shortness of breath, deep/rapid breathing, and sometimes jaundice; labs may show high lactate, rising transaminases, and an enlarged liver.
• Portal hypertension pattern: low platelets (first clue), a bigger spleen on exam or ultrasound, varices detected on endoscopy, and normal or near-normal synthetic function early on.
• Simple enzyme bump: asymptomatic ALT/AST rise on routine labs, which may settle with dose adjustment or a switch-if you catch it early.

Regulatory and guidelines context: The FDA and EMA flagged black-box warnings for lactic acidosis and severe hepatomegaly with steatosis. UK’s MHRA has echoed these risks in Drug Safety Updates. DHHS (2024), BHIVA (2023), and WHO (2022) guidelines place didanosine among agents to avoid when alternatives exist.

How to lower risk and monitor: a step‑by‑step plan

If didanosine is on the table-or still on your medication list-use a tight plan. Below is a practical approach used in HIV and hepatology clinics. It’s not a substitute for specialist care; it’s a working checklist so you don’t miss key steps.

Before starting or when reviewing existing therapy

1. Check baseline labs: ALT, AST, ALP, GGT, bilirubin, albumin, INR, CBC with platelets, creatinine/eGFR, hepatitis B surface antigen and core antibody, hepatitis C antibody/PCR if indicated.
2. Assess risks: prior didanosine exposure duration, history of pancreatitis, pregnancy status, BMI, alcohol use, and other hepatotoxins (including supplements).
3. Review interactions and avoid: allopurinol (contraindicated), ribavirin (contraindicated), stavudine (avoid; high toxicity), tenofovir (raises didanosine levels; usually avoid), hydroxyurea (heightens toxicity risk). In coinfection, coordinate with liver and HIV teams.
4. Document a stop rule: agree ahead of time when you’ll pause/stop didanosine (see thresholds below). Set up urgent contact routes.
5. Consider alternatives: Modern regimens with tenofovir alafenamide, tenofovir disoproxil, abacavir, lamivudine, or emtricitabine are preferred in current guidelines. Switch planning belongs with an HIV specialist.

During treatment

1. Monitoring schedule: repeat LFTs at 2-4 weeks, 8-12 weeks, then every 3-6 months if stable. Tighter intervals if you have hepatitis B/C, pregnancy, higher BMI, or any symptoms.
2. Watch the platelets: a falling platelet count with a growing spleen can be the earliest sign of portal hypertension.
3. Symptom watch list: jaundice, dark urine, right upper abdominal pain, unexplained fatigue, nausea/vomiting, deep or rapid breathing, new bruising/bleeding, abdominal swelling.
4. Alcohol and acetaminophen: keep alcohol to zero or near-zero while on didanosine; use paracetamol (acetaminophen) cautiously and within standard doses, especially if LFTs are high.
5. Pregnancy: avoid didanosine if at all possible; lactic acidosis risk is higher, particularly with stavudine (DHHS Perinatal Guidelines).

When to pause/stop or switch (typical clinic rules)

• ALT or AST >5× the upper limit of normal (ULN) even without symptoms.
• ALT or AST >3× ULN with symptoms (jaundice, abdominal pain, nausea), or bilirubin >2× ULN.
• Any signs of lactic acidosis (deep/rapid breathing, severe fatigue, abdominal pain) or lactate >2 mmol/L with symptoms.
• Platelets drifting down with splenomegaly or signs of portal hypertension-discuss urgent imaging and endoscopy screening with hepatology.

These thresholds align with common hepatology and HIV program practices (EASL DILI guidance; DHHS 2024; BHIVA 2023). Your specialist may tailor them to your situation.

Drug interactions that raise liver risk

• Allopurinol: contraindicated; boosts didanosine exposure, increasing toxicity.
• Ribavirin: contraindicated; linked to fatal lactic acidosis, pancreatitis, and liver failure with didanosine.
• Stavudine: avoid; additive mitochondrial toxicity.
• Tenofovir (TDF): raises didanosine levels; usually avoid co-administration.
• Hydroxyurea: avoid; higher risk of pancreatitis and hepatotoxicity.
• Alcohol and high-dose niacin or vitamin A: can worsen liver stress.

Decision steps if labs go off

1. Re-check LFTs within 48-72 hours to confirm the trend.
2. Look for a trigger: new meds, alcohol, viral hepatitis flare, dehydration, dose error.
3. Apply the stop rule. If criteria met, hold didanosine and inform the HIV team the same day.
4. Get a lactate level if symptoms suggest mitochondrial toxicity.
5. If platelets drop or spleen enlarges, order ultrasound and consider portal vein Doppler; loop in hepatology for possible elastography or endoscopy.

Real-world scenarios, data, and quick tools

Two brief cases to make this concrete.

• Case 1: Early mitochondrial signal: A woman in her early 30s on didanosine-stavudine develops nausea, deep breathing, and fatigue at week 8. LFTs are moderately raised; lactate is 3.1 mmol/L. Therapy is stopped the same day and switched under specialist care. She recovers fully and moves to a modern NRTI backbone. Lesson: symptoms + early lactate check saved her from a crash.
• Case 2: Silent portal pressure: A man in his 40s with long-term didanosine use feels fine, but platelets slip from 180 to 110 ×10⁹/L over a year. Ultrasound shows splenomegaly; elastography is normal-ish. Endoscopy finds small varices. Didanosine is discontinued; he starts nonselective beta-blockers. Lesson: falling platelets can be the first alarm bell for NCPH.

Key numbers at a glance (round figures from LiverTox, FDA/EMA product info, and HIV guidelines; exact rates vary by study and era):

Liver safety checklist

• Baseline and periodic LFTs, INR, platelets.
• Set and document stop rules; share them with the patient.
• Screen for hepatitis B/C and vaccinate for hepatitis B when indicated.
• Avoid flagged interactions: allopurinol, ribavirin, stavudine, hydroxyurea, tenofovir.
• Zero or near-zero alcohol while on didanosine.
• Educate on red flags: jaundice, severe abdominal pain, deep breathing, new bruising/bleeding.
• If platelets fall, check spleen size and consider NCPH workup.

UK/2025 context

In the UK, didanosine is rarely prescribed now. BHIVA and MHRA emphasize alternative regimens and close monitoring if legacy use continues. NHS clinics typically follow the lab schedule above, with faster follow-up for anyone with coinfection, pregnancy, or early warning symptoms. If you’re in shared care between HIV and hepatology, make sure both teams see the labs.

Evidence and sources behind these recommendations

• FDA/EMA prescribing information for didanosine (black-box warnings for lactic acidosis and severe hepatomegaly with steatosis).
• NIH LiverTox monograph on didanosine (patterns of injury, NRH/NCPH reports).
• DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents (2024 update; de-emphasis of didanosine).
• BHIVA Guidelines (2023) and MHRA Drug Safety Updates.
• WHO Consolidated HIV Guidelines (2022) and EASL guidance on drug-induced liver injury.

FAQs and next steps

What are the earliest signs I should not ignore?
Three standouts: new jaundice or dark urine; deep/rapid breathing with abdominal pain or profound fatigue (think lactic acidosis); and easy bruising or nosebleeds. Also pay attention to unexpected drops in platelets on routine labs.

Can past didanosine use cause problems now?
Yes. NRH/NCPH can show after years of exposure, sometimes even after stopping. If you have a history of long-term didanosine and new thrombocytopenia or splenomegaly, ask about portal hypertension workup.

How is noncirrhotic portal hypertension different from cirrhosis?
NCPH raises portal pressure without the classic scarring pattern of cirrhosis. Liver stiffness can be near-normal on elastography, but platelets are low, the spleen is big, and varices may be present. Biopsy can show nodular regenerative hyperplasia.

Is alcohol completely off the table?
While on didanosine, best to avoid alcohol. It adds stress to the liver and blurs the picture if enzymes rise. If you’ve had enzyme elevations or fatty liver, abstaining is the safer call.

What about pregnancy?
Didanosine is avoided in pregnancy, especially with stavudine, because of lactic acidosis risk. Per DHHS perinatal guidance, pick safer alternatives with your specialist team.

Which supplements should I be careful with?
Be wary of high-dose vitamin A, niacin, green tea extracts, and bodybuilding boosters-they can strain the liver. Always run supplements by your clinic pharmacist or doctor.

Can I just switch off didanosine?
Don’t stop on your own. Sudden gaps can cause viral rebound. Work with your HIV team on a planned switch to a safer modern regimen.

How often should I check labs if I’m stable?
If low risk and asymptomatic, every 3-6 months after the first three months. If you have hepatitis B/C, pregnancy, or any warning signs, increase the frequency.

Do I need imaging?
Not always. Ultrasound is helpful if platelets fall, the spleen feels enlarged, or enzymes stay up. Elastography and endoscopy are considered if NCPH is suspected.

Is this still relevant in 2025 if few people take didanosine?
Yes. Some people remain on legacy regimens, and many clinicians review old records. Past exposure can explain new portal hypertension findings today.

Quick next steps

• If you’re currently taking didanosine: check the date of your last LFTs. If it’s been more than 3 months-or you have symptoms-book tests now.
• If you used didanosine for years and now have low platelets or an enlarged spleen: mention NCPH to your clinician. Ask about ultrasound and GI referral for variceal screening.
• If your regimen includes any flagged interaction (allopurinol, ribavirin, stavudine, hydroxyurea, tenofovir): bring this up with your HIV pharmacist or doctor urgently.
• Write down a stop rule and emergency contact number. Keep it on your phone and on your fridge. It sounds simple, but it saves time when it counts.

If you want one line to remember, make it this: treat didanosine liver toxicity as preventable most of the time-if you monitor smartly, avoid the bad combinations, and act fast on red flags.