Should the Current Regimen Be Changed to TLD?
Yes, switching to TLD (tenofovir/lamivudine/dolutegravir) is strongly recommended if the patient is virologically suppressed on an older regimen, as TLD represents a guideline-preferred regimen with superior efficacy, tolerability, and high barrier to resistance. 1
Prerequisites That Must Be Confirmed Before Switching
Before making any regimen change, you must systematically review the following:
- Complete antiretroviral treatment history including all prior regimens and duration of use to identify any previous treatment failures 2, 1
- All prior resistance testing results (genotypic and phenotypic if available) to ensure no integrase strand transfer inhibitor (InSTI) or nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations are present 2, 1
- Current viral suppression status must be confirmed with HIV-1 RNA <50 copies/mL if switching from a suppressive regimen 1
- Hepatitis B virus (HBV) co-infection status because if HBV-positive, tenofovir-containing regimens are mandatory to maintain HBV suppression 2, 1
- Renal function assessment including estimated glomerular filtration rate (eGFR) to determine whether TAF or TDF formulation is appropriate 1
When Switching to TLD Is Most Appropriate
For patients with viral suppression on older regimens, switching to TLD is recommended to reduce pill burden, minimize long-term toxicities, simplify dosing, or address patient preference—provided no documented NRTI or InSTI resistance mutations exist 2, 1. The 2018 IAS-USA guidelines explicitly state that if an older regimen is well tolerated without evidence of toxicity, there is little reason to switch, but patients should be questioned carefully to identify subtle adverse effects they may not attribute to the medication 2.
For patients with virologic failure on NNRTI-based first-line regimens, TLD is specifically recommended as second-line therapy 1, 3. Research demonstrates that 85% of adults switching to TLD achieved virologic suppression at 24 weeks despite substantial baseline NRTI resistance, with 89% having resistance to tenofovir and/or lamivudine 3. Extended follow-up to 72 weeks showed maintained efficacy with 75% achieving <50 copies/mL 4.
Choosing Between TAF and TDF Formulations
Tenofovir alafenamide (TAF) is preferred over tenofovir disoproxil fumarate (TDF) for most patients due to reduced renal and bone toxicity 1. Specifically:
- Use TAF/lamivudine/dolutegravir for patients with or at risk for kidney disease (eGFR <60 mL/min/1.73 m²) or bone disease (osteopenia/osteoporosis) 2, 1
- TDF can be used if TAF is unavailable or cost is prohibitive, particularly if the patient does not have or is not at high risk for kidney or bone disease 2
- Proactive switching from TDF to TAF is recommended for patients at high risk of renal or bone toxicity 2
Critical Clinical Scenarios Requiring Special Consideration
For pregnant patients or those planning pregnancy, dolutegravir with TAF/lamivudine is the recommended regimen with high antiviral efficacy and low rates of adverse birth outcomes 1. Note that earlier concerns about potential teratogenicity when dolutegravir is initiated before conception have been addressed in updated guidelines 2.
For tuberculosis co-infection, dolutegravir dosing must be increased to 50 mg twice daily during active tuberculosis treatment with rifampin to overcome drug interactions 2, 1. Alternatively, efavirenz (600 mg/day) or raltegravir (800 mg twice daily) can be used with rifamycin-based tuberculosis regimens 2.
For HBV co-infection, patients must receive a regimen containing two drugs active against HBV—typically tenofovir (TAF or TDF) plus lamivudine—and should generally not be switched to 2-drug ART regimens 2, 1. Discontinuing tenofovir without alternative HBV suppressive therapy risks hepatitis flare 1.
Post-Switch Monitoring Protocol
After switching to TLD, implement the following monitoring schedule:
- HIV-1 RNA at 1 month to confirm maintained or achieved viral suppression 2, 1
- HIV-1 RNA every 3 months for the first year, then at least every 6 months if stable 2, 1
- Renal function monitoring (serum creatinine and eGFR), particularly if using TDF 1
- Bone density assessment if risk factors are present and TDF is used 1
- Adherence support as transition from other regimens may require counseling 1
Common Pitfalls to Avoid
Never switch without reviewing complete resistance testing history, as this may compromise efficacy and lead to treatment failure 1. In patients with NRTI mutations, switching to a regimen containing a drug with low genetic barrier to resistance is explicitly not recommended 2.
Do not use TLD in patients with documented integrase resistance without expert consultation, as dolutegravir may require twice-daily dosing or combination with other fully active agents 2.
Avoid switching if eGFR <30 mL/min/1.73 m² without dose adjustment of individual components 1. TDF is specifically not recommended for individuals with or at risk for kidney or bone disease 2.
For patients failing on TLD, resistance testing is mandatory while taking the failing regimen or within 4 weeks of stopping 2. A boosted protease inhibitor plus 2 NRTIs (with at least 1 active NRTI) is recommended for initial treatment failure of an InSTI-containing regimen 2.
Evidence Supporting TLD as Second-Line After First-Line Failure
Research from South Africa demonstrates that recycling tenofovir and lamivudine with dolutegravir is highly effective even when patients have baseline NRTI resistance 3, 4. At 24 weeks, 83% of patients with resistance to both tenofovir and lamivudine achieved virologic suppression 3. Importantly, no integrase-inhibitor resistance was detected despite low-level viremia in a minority of participants through 72 weeks 4.
However, a cautionary note from Zimbabwe shows that among adolescents with virologic failure on TLD, 90% were already failing on their previous regimens before the switch 5. This underscores the critical importance of confirming viral suppression or addressing adherence issues before transitioning to TLD 5.