What are the potential interactions between acetaminophen and antiretroviral therapy (ART) in patients with HIV, particularly those with pre-existing liver disease or taking protease inhibitors (PIs) like ritonavir or non-nucleoside reverse transcriptase inhibitors (NNRTIs) like efavirenz?

Acetaminophen Interactions with HIV Drugs

Acetaminophen has minimal direct pharmacokinetic interactions with antiretroviral therapy (ART) because it is not significantly metabolized through the cytochrome P450 pathways that are affected by most HIV medications. However, the primary concern is additive hepatotoxicity, particularly in patients with pre-existing liver disease or those taking hepatotoxic antiretrovirals.

Key Interaction Considerations

Hepatotoxicity Risk with Specific ART Agents

The most critical concern is overlapping liver toxicity rather than direct drug-drug interactions.

• Protease inhibitors (PIs) can cause hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice, with increased risk in patients with underlying hepatitis B or C 1.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs), particularly nevirapine, are associated with hepatotoxicity with an incidence of 12.5% and risk of fulminant hepatic necrosis and death 2.
• Efavirenz causes unique neuropsychiatric effects but also carries hepatotoxicity risk 2.

Ritonavir and Cobicistat Considerations

Ritonavir is the most potent CYP3A4 inhibitor among all protease inhibitors 1, 3, but acetaminophen is primarily metabolized via glucuronidation and sulfation, not CYP3A4, making direct pharmacokinetic interactions unlikely 3, 4.

• However, ritonavir causes substantial hepatotoxicity risk, and caution should be exercised when combining with acetaminophen in patients with pre-existing liver disease 1.
• Increased AST/ALT monitoring should be considered, especially during the first three months of ritonavir treatment 1.

Clinical Management Algorithm

For patients on ART requiring acetaminophen:

1. Assess baseline liver function before initiating acetaminophen in any patient on PIs (especially ritonavir-boosted regimens) or NNRTIs (especially nevirapine) 1, 2.

2. Limit acetaminophen dose to ≤2 grams per day (rather than the standard 4 grams) in patients with:

   • Pre-existing liver disease 1
   • Hepatitis B or C co-infection 1
   • Current use of ritonavir, cobicistat, or nevirapine 1, 2

3. Monitor liver enzymes monthly for the first 3 months when combining acetaminophen with hepatotoxic ART, then every 3 months thereafter 1.

4. Discontinue acetaminophen immediately if AST/ALT rises above 3 times baseline or if clinical signs of hepatitis develop (nausea, vomiting, jaundice, right upper quadrant pain) 1.

Preferred ART Regimens When Acetaminophen is Needed

Integrase strand transfer inhibitors (INSTIs) have the most favorable safety profile with the fewest drug interactions and minimal hepatotoxicity 2, 5.

• Bictegravir, dolutegravir, and raltegravir-based regimens are preferred when chronic acetaminophen use is anticipated 6, 5.
• These agents avoid the CYP3A4 inhibition seen with PIs and the hepatotoxicity concerns with NNRTIs 6, 5.

Special Populations

In patients with hepatitis B or C co-infection:

• Select an ART regimen that treats both HIV and hepatitis B 5.
• Use acetaminophen with extreme caution and at reduced doses (≤2 grams daily) 1.
• Consider alternative analgesics when possible 1.

In pregnant patients:

• Ritonavir oral solution should be avoided due to ethanol content 1.
• Acetaminophen remains the preferred analgesic in pregnancy, but dose limitation to ≤3 grams daily is prudent when combined with any hepatotoxic ART 1.

Common Pitfalls to Avoid

• Do not assume acetaminophen is completely safe simply because it lacks CYP450-mediated interactions with ART 1, 3.
• Never exceed 2 grams daily of acetaminophen in patients on ritonavir, cobicistat, or nevirapine with any degree of liver dysfunction 1, 2.
• Do not overlook alcohol use, as the combination of alcohol, acetaminophen, and hepatotoxic ART creates compounded liver injury risk 1.
• Avoid assuming all NRTIs are safe with acetaminophen—while they lack CYP450 interactions, some (like zidovudine) cause other toxicities that may complicate clinical management 2, 7.

Monitoring Requirements

Establish a systematic monitoring protocol:

• Baseline liver function tests before initiating acetaminophen in any patient on PIs or NNRTIs 1.
• Monthly AST/ALT for first 3 months, then every 3 months 1.
• Immediate evaluation if symptoms of hepatotoxicity develop (nausea, vomiting, abdominal pain, jaundice) 1.
• Consider checking acetaminophen levels if overdose is suspected, particularly in patients with altered mental status on efavirenz (which causes neuropsychiatric effects) 2.