Long-term HIV Viral Suppression with TLD Despite Transmitted Dolutegravir and Lamivudine Resistance

Overview

A patient with transmitted multi-class HIV drug resistance, including major resistance mutations to dolutegravir (DTG) and lamivudine (3TC), achieved and maintained viral suppression for over three years on a co-formulated regimen of tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Pharmacologic and phenotypic analyses indicated that higher DTG drug concentrations overcame resistance mutations.

Background

Integrase strand transfer inhibitors (INSTIs) like dolutegravir are recommended in most first-line HIV treatment regimens due to their efficacy and high barrier to resistance. Transmitted INSTI resistance is rare, and data on treatment outcomes in such cases are limited. The HPTN 083 trial evaluated HIV prevention strategies and identified a participant with transmitted INSTI resistance who was treated successfully with TLD. This case provides insights into managing transmitted multi-class resistance including INSTI resistance.

Data Highlights

Key Findings

• The participant had transmitted multi-class HIV drug resistance including major INSTI mutations G140S and Q148H, conferring high-level resistance to dolutegravir and lamivudine.
• Despite resistance, initiation of TLD regimen 3 weeks after diagnosis led to viral load decline from over 1 million copies/mL to <40 copies/mL within 11 months.
• Viral suppression was sustained for more than 3 years on TLD without treatment failure.
• Phenotypic testing showed the virus retained susceptibility to dolutegravir at higher drug concentrations.
• Pharmacologic data confirmed dolutegravir plasma levels were adequate to overcome the resistance mutations.
• Single-genome sequencing confirmed persistence of resistance mutations but no emergence of new resistance during treatment.

Clinical Implications

This case demonstrates that transmitted INSTI resistance does not preclude successful long-term viral suppression with a dolutegravir-based regimen when drug concentrations are sufficient. It highlights the importance of adherence to maintain therapeutic drug levels capable of overcoming resistance. Routine genotyping prior to ART initiation remains important but may not always be feasible; close viral load monitoring is essential to detect treatment failure early.

Conclusion

In a patient with transmitted multi-class HIV resistance including to dolutegravir and lamivudine, sustained viral suppression was achieved and maintained for over three years on TLD. Adequate dolutegravir drug exposure can overcome certain INSTI resistance mutations, supporting the continued use of dolutegravir-based regimens in similar cases.

References

1. HPTN 083 Trial Publications 2019-2021 -- Efficacy and Safety of CAB-LA vs TDF/FTC
2. Surveillance of Transmitted Drug Resistance Mutations -- WHO Guidelines