What are the common side effects of antiretroviral (ARV) post‑exposure prophylaxis regimens such as bictegravir/emtricitabine/tenofovir alafenamide or dolutegravir combined with tenofovir alafenamide or tenofovir disoproxil fumarate plus emtricitabine or lamivudine?

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Common Side Effects of ARV Post-Exposure Prophylaxis

The most common side effects of modern ARV post-exposure prophylaxis regimens are gastrointestinal symptoms (nausea, diarrhea, abdominal discomfort), fatigue, and headache, with INSTI-based regimens like bictegravir/emtricitabine/tenofovir alafenamide or dolutegravir-based combinations being significantly better tolerated than older PI-based or NNRTI-based regimens. 1

INSTI-Based Regimens (Preferred for PEP)

Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)

The most frequently reported side effects include:

  • Gastrointestinal: Abdominal discomfort/pain, gas or bloating (42%), diarrhea (38%) 2
  • Systemic: Fatigue (28%), nausea or vomiting (28%) 2
  • Neurologic: Headache (14%), dizziness or lightheadedness (6%) 2

Critical point: These symptoms are typically mild, self-limited, and rarely result in medication discontinuation. In one study, 71% of participants completed the full 28-day PEP course 2.

Dolutegravir + Tenofovir/Emtricitabine (DTG + TDF/FTC or TAF/FTC)

Common side effects include:

  • Gastrointestinal: Nausea (25%), diarrhea (21%) 3, 4
  • Systemic: Fatigue (26%), headache (10-15%) 3, 4
  • Musculoskeletal: Myalgias or arthralgias (8%) 4

Completion rates are excellent: 90% in one study, with only 1% discontinuing due to adverse events (headache) 3. Studies comparing DTG-based regimens with protease inhibitor regimens show significantly fewer side effects with INSTIs (p<0.0001) 1.

PI-Based Regimens (Alternative Options)

Darunavir/ritonavir (DRV/r) + TDF/FTC

Common side effects include:

  • Gastrointestinal: Fatigue, nausea, diarrhea, loss of appetite 1
  • Dermatologic: Skin rash (usually mild-to-moderate, self-limited) 1
  • Hepatic: Elevated liver transaminases 1
  • Neurologic: Headache 1

Important caveat: While DRV/r is better tolerated than older PIs (lopinavir/ritonavir, atazanavir), studies comparing DRV/r with INSTIs show significantly more side effects with DRV/r (p<0.0001) 1. Class-specific PI effects include metabolic complications (insulin resistance, diabetes, dyslipidemia, lipodystrophy) and hepatotoxicity, though these are less relevant for short-term PEP use 1.

NNRTI-Based Regimens (Generally Avoided for PEP)

Rilpivirine/FTC/TDF (RPV/FTC/TDF)

Up to 88% of participants report one or more adverse events, including:

  • Systemic: Fatigue, dizziness 1
  • Gastrointestinal: Nausea, gastrointestinal intolerance 1
  • Neurologic: Headache, sleep disorders 1
  • Laboratory: Elevated creatinine 1

Most adverse events are mild and self-limited with few premature discontinuations 1.

Efavirenz-Based Regimens

These are associated with higher discontinuation rates due to:

  • CNS toxicity: Severe dizziness, psychiatric side effects, depression 1
  • Hepatic: Elevated transaminases, fulminant hepatitis 1
  • Cardiac: QT interval prolongation 1
  • Dermatologic: Rash 1
  • Metabolic: Hyperlipidemia 1

Efavirenz should be avoided in persons with severe liver disease (Child-Pugh B/C) and psychiatric illness 1.

NRTI Backbone Side Effects

Tenofovir Disoproxil Fumarate (TDF)

  • Renal: Decreased eGFR (mean decrease 14 ml/min/1.73m² at day 28), rare cases of Fanconi's syndrome 5, 3
  • Bone: Decreased bone mineral density 5
  • Gastrointestinal: Nausea, diarrhea 5

Tenofovir Alafenamide (TAF)

TAF is associated with less renal and bone toxicity compared to TDF due to lower plasma tenofovir concentrations 1. However, TAF may be associated with:

  • Metabolic: Higher blood lipid levels than TDF 1
  • Weight: Greater weight gain compared to TDF-containing regimens 6

Emtricitabine (FTC) and Lamivudine (3TC)

Both are well tolerated with no significant treatment-limiting adverse effects 1. Rarely, 3TC has been associated with pancreatitis, with higher risk in children 1.

Key Clinical Pitfalls to Avoid

  1. Don't underestimate completion rates: INSTI-based regimens have 70-90% completion rates versus 39-57% for older regimens 2, 4

  2. Monitor renal function with TDF: Expect a transient decrease in eGFR (approximately 14 ml/min/1.73m²), but watch for eGFR <60 ml/min/1.73m² (occurred in 3% of patients) 3

  3. Counsel about timing of side effects: Most adverse events occur within the first month, though approximately 25% may be reported after 1 year of treatment 7

  4. Drug-drug interactions: Boosted-PI regimens (with ritonavir or cobicistat) have the greatest potential for drug-drug interactions due to CYP3A inhibition 1

  5. Sex differences exist: Male patients report more adverse events overall, with differences in signal spectrum between sexes 7

References

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