Can ritonavir (100 mg twice daily as part of antiretroviral therapy) cause acute pancreatitis?

Ritonavir and Pancreatitis Risk

Yes, ritonavir can cause acute pancreatitis, though it is a relatively rare adverse effect occurring through multiple mechanisms including drug-induced hypertriglyceridemia and direct pancreatic toxicity. 1

Evidence from Guidelines

The strongest guideline evidence comes from multiple sources documenting ritonavir's association with pancreatitis:

• Lopinavir-ritonavir is explicitly known to cause pancreatitis as documented in Military Medical Research guidelines, which list pancreatitis among the serious adverse effects alongside liver injury, leukopaenia, anaemia, severe cutaneous eruptions, and QT prolongation. 1

• The Korean Association for the Study of the Liver (KASL) guidelines specifically warn that severe lactic acidosis, steatosis, and pancreatitis have been reported in patients taking certain antiretroviral combinations, though this was primarily documented with didanosine plus ribavirin rather than ritonavir alone. 1

• The National Comprehensive Cancer Network (NCCN) guidelines acknowledge that acute pancreatitis has been observed with immune checkpoint inhibitors and note that autoimmune diseases including pancreatitis have been reported with lopinavir-ritonavir, recommending against its use if immune checkpoint inhibitors are continued. 1

Mechanism and Clinical Context

Ritonavir causes pancreatitis through two primary mechanisms:

• Hypertriglyceridemia-induced pancreatitis: Ritonavir is a potent CYP3A4 inhibitor that causes lipodystrophy and combined hyperlipidemias, which can trigger severe hypertriglyceridemia leading to acute pancreatitis. 2 A documented case showed triglyceride levels reaching 62.9 mmol/L after just 3 weeks of ritonavir treatment, resulting in acute pancreatitis requiring plasmapheresis. 2

• Direct pancreatic toxicity: Beyond lipid-mediated effects, ritonavir may cause direct inflammatory injury to pancreatic parenchyma. 3

Clinical Recognition and Monitoring

Monitor for these prodromal symptoms that precede severe pancreatitis: 4

• Abdominal distention and pain
• Nausea and vomiting
• Diarrhea and anorexia
• Dyspnea and generalized weakness
• Unexplained weight loss

If symptoms develop, check lipase levels immediately (≥2.1 times upper limit of normal indicates pancreatitis). 4

Management Algorithm

If pancreatitis develops:

1. Discontinue ritonavir immediately as recommended by the WHO. 4

2. Provide supportive care for acute pancreatitis management. 5

3. In cases of severe hypertriglyceridemia-induced pancreatitis (triglycerides >62 mmol/L), consider plasmapheresis for rapid lipid reduction, which has demonstrated dramatic declines in cholesterol, triglycerides, lipase, and amylase levels within days. 2

4. Do not rechallenge with ritonavir after resolution, as recurrent pancreatitis upon rechallenge is well-documented. 5

Risk Stratification

Higher-risk populations include: 5

• Children
• Women
• Elderly patients
• Patients with advanced HIV infection
• Those with pre-existing inflammatory bowel disease

The incidence of drug-induced pancreatitis overall is estimated at 0.1-2%, making ritonavir-associated pancreatitis relatively uncommon but clinically significant when it occurs. 5

Important Caveats

• Most cases of drug-induced pancreatitis are mild, but severe and even fatal cases may occur, making identification of the offending agent critical. 5

• The diagnosis is challenging because there are no unique clinical characteristics to distinguish drug-induced pancreatitis from other etiologies—you must exclude common causes (gallstones, alcohol, hypertriglyceridemia from other causes) and establish temporal relationship with drug initiation. 5

• Recent case reports document pancreatitis with Paxlovid (nirmatrelvir-ritonavir combination), suggesting the ritonavir component maintains this risk even at the lower boosting doses used in COVID-19 treatment. 3

• The evidence linking ritonavir to pancreatitis is primarily from case reports and case series rather than large randomized trials, but the temporal relationship, response to withdrawal, and documented rechallenge reactions provide strong causative evidence. 2, 5, 6