What are the potential drug-to-drug interactions with a Tenofovir (TDF), Lamivudine (3TC), Dolutegravir (DTG) (TLD) antiretroviral regimen and other medications?

Drug-to-Drug Interactions with TLD (Tenofovir/Lamivudine/Dolutegravir) Regimen

The TLD regimen has minimal drug-drug interactions compared to protease inhibitor or NNRTI-based regimens because dolutegravir is metabolized independently of the CYP450 pathway, making it the preferred choice when drug interactions are a concern. 1

Key Advantages of TLD for Minimizing Drug Interactions

• Dolutegravir-based regimens (including TLD) are specifically recommended to minimize drug-drug interactions in patients requiring chemotherapy, immunosuppressive therapy for transplantation, or treatment for autoimmune diseases because integrase inhibitors like dolutegravir are metabolized independently of CYP450 enzymes 1.

• Tenofovir and lamivudine do not require dose adjustment in patients with severe hepatic impairment and have minimal metabolic interactions, further reducing the interaction potential of the TLD regimen 1.

• The TLD combination has no clinically significant interactions with most common medications, including raltegravir, maraviroc, rilpivirine, and sofosbuvir-based hepatitis C regimens 2.

Specific Drug Interactions Requiring Attention

Hepatitis C Co-Treatment

• Sofosbuvir-based regimens have no clinically significant interactions with tenofovir, emtricitabine (similar to lamivudine), or dolutegravir, making TLD an excellent choice for HCV/HIV coinfection 1.

• When using ledipasvir/sofosbuvir with TLD, monitor renal function every 2-4 weeks because ledipasvir increases tenofovir levels through P-glycoprotein inhibition, potentially increasing renal toxicity risk, particularly in patients with creatinine clearance 30-60 mL/min 1.

• Ombitasvir/paritaprevir/ritonavir plus dasabuvir can be safely used with tenofovir, lamivudine, and dolutegravir without dose adjustments 1.

Acid-Reducing Agents

• Dolutegravir absorption is not significantly affected by acid-reducing agents, unlike other integrase inhibitors, so proton pump inhibitors and H2-receptor antagonists can be used without dose separation or adjustment 3.

Enzyme Inducers

• Rifampin and other potent CYP3A/UGT1A1 inducers require dolutegravir dose increase to 50 mg twice daily (instead of the standard 50 mg once daily in TLD) to maintain adequate drug levels 3.

• Avoid carbamazepine, phenobarbital, phenytoin, and St. John's wort with dolutegravir, as these strong inducers may significantly reduce dolutegravir exposure and compromise virologic efficacy 1.

Immunosuppressive Medications (Transplant Patients)

• TLD is the preferred regimen for solid organ transplant recipients because it avoids the significant drug-drug interactions between protease inhibitors/boosters and tacrolimus/cyclosporine that complicate immunosuppression management 1.

• Dolutegravir/lamivudine combinations minimize risks of drug-drug interactions in transplant settings and can be used in patients without archived drug resistance 1.

Cation-Containing Supplements

• Polyvalent cations (calcium, iron, magnesium, aluminum) can reduce dolutegravir absorption by chelation, but this can be managed by taking dolutegravir 2 hours before or 6 hours after these supplements, or by taking them together with food 4.

Renal Monitoring Considerations

• Dolutegravir causes a 10% increase in serum creatinine through blockade of tubular secretion without affecting true glomerular filtration rate, so expect this benign increase when monitoring renal function 3.

• Monitor renal function every 3-6 months in patients on TLD, particularly when combined with medications that increase tenofovir exposure (such as ledipasvir or protease inhibitors if switching regimens) 3.

Contraindications and Special Populations

• TLD is absolutely contraindicated in patients with active hepatitis B coinfection because the regimen lacks adequate HBV coverage and risks hepatitis flares; these patients require a tenofovir-based regimen plus lamivudine or emtricitabine with additional HBV-active agents 3.

• Patients with documented integrase inhibitor resistance should not use TLD as the regimen lacks sufficient genetic barrier in this setting 3.

Common Medications Safe with TLD

• Statins (including rosuvastatin), bisphosphonates (risedronate), calcium/vitamin D supplements, and most cardiovascular medications have no significant interactions with TLD 4.

• Most anticoagulants, including warfarin and direct oral anticoagulants, can be used with TLD without dose adjustment, unlike protease inhibitor-based regimens 2.

Clinical Monitoring Algorithm

When prescribing TLD, follow this systematic approach:

1. Screen for active hepatitis B infection - if positive, TLD is contraindicated 3
2. Review all concomitant medications for strong CYP/UGT inducers - if present, increase dolutegravir to twice daily dosing 3
3. Assess baseline renal function - avoid if creatinine clearance <30 mL/min 3
4. If adding hepatitis C treatment with ledipasvir/sofosbuvir, establish renal monitoring every 2-4 weeks 1
5. Check HIV RNA at 4 weeks after any regimen switch to TLD to confirm maintained suppression 4
6. Monitor renal function every 3-6 months and expect a small creatinine increase from dolutegravir 3

Key Clinical Pitfall to Avoid

The most common error is failing to recognize that the small creatinine increase with dolutegravir (approximately 0.1-0.2 mg/dL) is not true renal injury but rather inhibition of tubular creatinine secretion - do not unnecessarily discontinue TLD based on this benign laboratory change alone 3.