Switching to TLD After ZLN Failure: Recommended with Caveats
Yes, switching to TLD (Tenofovir/Lamivudine/Dolutegravir) after ZLN (Zidovudine/Lamivudine/Nevirapine) failure is appropriate and effective, but requires resistance testing first and recognition that NRTI resistance may persist despite good virologic outcomes. 1
Key Recommendation Based on Strongest Evidence
For failure of an initial NNRTI-based regimen like ZLN, dolutegravir plus NRTIs is superior to boosted PI-based regimens when the next regimen includes at least one active NRTI. 1 This makes TLD a preferred second-line option after ZLN failure, even though both tenofovir and lamivudine are being "recycled" from the failed regimen. 2
Critical Pre-Switch Requirements
Mandatory Resistance Testing
Perform genotypic resistance testing while the patient is still on the failing ZLN regimen or within 4 weeks of stopping. 1 This identifies NRTI mutations (particularly M184V for lamivudine and K65R/K70E for tenofovir) and confirms NNRTI resistance patterns. 1
Review the complete antiretroviral treatment history and all prior resistance test results to ensure no archived integrase resistance that would compromise dolutegravir efficacy. 3
Confirm Virologic Failure
- Document two consecutive viral loads >1000 copies/mL before switching, as transient viral blips do not constitute true virologic failure. 2, 4
Evidence Supporting TLD After ZLN Failure
High Efficacy Despite NRTI Resistance
The most compelling evidence comes from a 2021 South African study specifically examining TLD as second-line therapy after tenofovir-based first-line failure: 2
85% (51/60) achieved viral suppression <50 copies/mL at week 24 despite 89% having baseline resistance to tenofovir and/or lamivudine. 2
Among those with resistance to BOTH tenofovir and lamivudine, 83% (29/35) still achieved virologic suppression, demonstrating that dolutegravir's high barrier to resistance can overcome NRTI resistance. 2
No integrase mutations emerged in the single participant who did not suppress, indicating dolutegravir maintains its potency even with compromised NRTI backbone. 2
Comparative Trial Data
The NADIA trial (2022) provides additional support for dolutegravir-based second-line regimens: 4
At 96 weeks, 90% on dolutegravir-based regimens maintained HIV-1 RNA <400 copies/mL, demonstrating durable efficacy. 4
Tenofovir-containing regimens were superior to zidovudine-containing regimens (92% vs 85% suppression, p=0.019), supporting the use of tenofovir in TLD even after first-line tenofovir exposure. 4
However, 9 participants (4%) developed dolutegravir resistance in second-line use, highlighting the importance of adherence support. 4
Practical Implementation Algorithm
Step 1: Obtain Resistance Testing
- Send genotypic resistance test while patient is on failing ZLN regimen 1
- Review for NNRTI mutations (expected with nevirapine failure) 1
- Document NRTI mutations, particularly M184V and tenofovir-associated mutations 2
Step 2: Assess for Contraindications
- Screen for hepatitis B surface antigen (HBsAg) - if positive, TLD is appropriate as it maintains HBV coverage 3
- Verify no prior integrase inhibitor exposure or resistance 3
- Check for pregnancy or pregnancy potential (dolutegravir can be used but requires counseling about neural tube defect risk in first trimester) 1
Step 3: Switch Directly to TLD
- No need to add extra dolutegravir dosing when switching from nevirapine (unlike efavirenz, nevirapine is not a strong CYP3A4 inducer requiring dolutegravir dose adjustment) 2
- Standard TLD dosing: TDF 300mg/3TC 300mg/DTG 50mg once daily 2
Step 4: Early Monitoring
- Check viral load at 4 weeks post-switch to ensure early virologic response 1
- Repeat at 12 and 24 weeks to confirm sustained suppression 2
- Monitor adherence closely, as dolutegravir resistance can emerge with suboptimal adherence in second-line use 4
Critical Pitfalls to Avoid
Don't Switch Without Resistance Testing
Never switch to TLD without documented resistance testing from the failing regimen. 1 While dolutegravir can overcome NRTI resistance, undetected integrase mutations from prior undisclosed treatment would lead to rapid failure. 3
Don't Assume NRTI Resistance Precludes TLD Use
The presence of M184V or tenofovir resistance mutations does NOT contraindicate switching to TLD. 2 The high genetic barrier of dolutegravir compensates for reduced NRTI activity, with 83% suppression rates even with dual NRTI resistance. 2
Don't Use Single-Dose Dolutegravir
Standard 50mg once-daily dolutegravir dosing is appropriate for ZLN failure. 2 Twice-daily dosing (100mg total) is only required when integrase resistance mutations are present, which would not be expected after first-line NNRTI failure. 1
Don't Overlook Adherence Support
The 4% dolutegravir resistance rate in second-line use (compared to <1% in first-line) emphasizes the critical importance of adherence counseling. 4 Patients who failed ZLN may have adherence challenges that must be addressed before switching. 1
Alternative Considerations
When TLD May Not Be Optimal
If significant renal impairment exists (CrCl <50 mL/min), consider abacavir/lamivudine/dolutegravir instead, provided HLA-B*5701 is negative. 1
If the patient has documented poor adherence, consider a boosted PI-based regimen (darunavir/ritonavir with NRTIs) which has a higher genetic barrier in the setting of adherence challenges, though dolutegravir-based regimens remain superior for efficacy. 1, 4
Long-Term Outcomes
Real-world data from rural Zimbabwe showed 95% virologic suppression among children and adolescents switched to TLD after a median of 6.9 months, including those failing boosted PI regimens. 5 This demonstrates TLD's effectiveness across diverse populations and prior treatment histories. 5
The TANGO study, while examining treatment-experienced patients switching from suppressive regimens rather than virologic failure, demonstrated durable efficacy through 144 weeks with DTG/3TC, supporting the long-term viability of dolutegravir-based two-drug regimens. 6