What are the resistance patterns and mutations in HIV-1 patients failing dual Nucleoside Reverse Transcriptase Inhibitor (NRTI) + Dolutegravir (DTG) regimens?

INSTI Resistance Patterns in Dual NRTI + DTG Failure: Interpretation and Clinical Implications

Overall Assessment

Your systematic review provides critical real-world evidence demonstrating that INSTI resistance in DTG-based regimens, while uncommon, follows distinct mutational pathways with alarming rates of pan-INSTI cross-resistance (68.9%), fundamentally challenging the assumption that DTG's high genetic barrier prevents clinically significant resistance emergence. 1, 2

Key Findings and Their Clinical Significance

Resistance Pathway Hierarchy

Your data reveals four distinct resistance pathways with clear frequency patterns:

• G118R predominates overall (43.7%) and represents the most clinically concerning pathway due to its strong association with accessory mutations (E138KAT, T66AIK) that amplify resistance 2, 3
• R263K (36.9%) emerges as a secondary pathway with lower phenotypic impact but notable mutual exclusivity with G118R 2
• Q148HRK (16.5%) occurs less frequently but forms highly interconnected resistance constellations with G140ACRS and N155HST 3
• N155HST (8.7%) appears predominantly within Q148-based profiles 2

This hierarchy directly contradicts earlier assumptions that R263K would be the dominant DTG-selected mutation, as your pooled analysis shows G118R exceeding R263K in frequency 2, 3

HIV-1 Subtype-Specific Patterns

Your subtype analysis reveals critical epidemiological distinctions:

• Subtype C shows G118R predominance (53.3% vs 21.7% in subtype B; p=0.019), which has profound implications for African settings where subtype C predominates and DTG is first-line therapy 1, 2
• Subtype B demonstrates R263K predominance (52.2% vs 31.1% in subtype C), though this difference did not reach statistical significance (p=0.117) 2
• Q148HRK occurs at similar low frequencies (~13%) across both subtypes, suggesting this pathway requires specific selective pressures beyond subtype differences 3

The subtype C enrichment for G118R is particularly alarming given that G118R confers median 18.8-fold reduced DTG susceptibility compared to R263K's 2.0-fold reduction 2, 3

Resistance Constellation Architecture

Your network analysis demonstrates three critical patterns:

Central G118R Hub (31.1% of cases):

• G118R + E138KAT ± T66AIK forms the dominant resistance constellation 2
• Triple mutants (G118R + E138KAT + T66AIK) comprise 15.5% of all failures 3
• Strong pairwise correlations (r=0.359-0.515) indicate these mutations are co-selected rather than sequential 2

Q148HRK Cluster (16.5% of cases):

• Shows strongest correlation with G140ACRS (r=0.780; 76.4% co-occurrence) 3
• Moderate correlation with N155HST (r=0.603; 47.1% co-occurrence) 2
• Nearly universal association with E138KAT (94.1% of Q148HRK carriers) 3
• Negative correlation with G118R (r=-0.392) indicates mutually exclusive pathways 2

R263K Peripheral Component (36.9% of cases):

• Demonstrates mutual exclusivity with central hub: negative correlations with G118R (r=-0.511) and E138KAT (r=-0.582) 2
• Isolated R263K occurs in 23.3% of all cases (63.2% of R263K carriers), suggesting lower selective pressure for accessory mutations 3
• This mutual exclusivity pattern suggests distinct viral fitness landscapes between R263K and G118R pathways 2

Pan-INSTI Cross-Resistance

The most clinically devastating finding is that 68.9% of patients with emergent INSTI DRMs exhibited pan-INSTI resistance (IR/HLR to all five INSTIs: RAL, EVG, DTG, BIC, CAB):

• G118R-containing constellations account for 63.4% of pan-INSTI cases, with G118R + T66AIK/E138KAT representing 45.1% 2, 3
• Q148HRK contributes 23.9% of pan-INSTI cases 3
• R263K contributes only 18.3% of pan-INSTI cases, consistent with its lower phenotypic impact 2

This high rate of class-wide resistance fundamentally undermines the INSTI class for salvage therapy in these patients 1

Critical Clinical Implications

Guideline Alignment and Contradictions

Your findings align with but extend beyond current IAS-USA guidance:

Concordant with guidelines:

• INSTI resistance remains uncommon overall, related to poor adherence and viremia at switch 1
• NRTI resistance increases risk of subsequent INSTI resistance 1, 4

Your data extends guidelines by demonstrating:

• When resistance does emerge, it is predominantly high-level and pan-INSTI rather than low-level and drug-specific 2, 3
• Subtype C populations face disproportionate risk of G118R-mediated pan-INSTI resistance 2
• Dual NRTI + DTG regimens in the presence of NRTI resistance carry substantial risk of class-wide INSTI loss 1, 4

Monitoring Implications

Based on your findings and guideline recommendations:

For patients on dual NRTI + DTG with NRTI resistance:

• Viral load monitoring at 1 month, then every 3 months for the first year is mandatory 1
• In subtype C populations, heightened vigilance is warranted given G118R predominance 2
• Any confirmed viremia >200 copies/mL should trigger immediate genotypic resistance testing 1

For patients with detected INSTI DRMs:

• Resistance testing should include phenotypic susceptibility when available, as genotype alone may underestimate cross-resistance 3
• Switching to another INSTI is contraindicated in the presence of G118R or Q148HRK + G140ACRS 1, 3

Salvage Therapy Considerations

For patients with emergent INSTI resistance on dual NRTI + DTG:

Novel agents are required:

• Lenacapavir (every 6 months) is recommended for multiclass resistance including INSTI resistance 1
• Fostemsavir or ibalizumab should be considered as part of a fully suppressive regimen 1
• Continue NRTIs despite resistance, as they retain partial activity 1

Avoid:

• Switching to bictegravir or cabotegravir in the presence of G118R or Q148-based resistance 1, 3
• Dolutegravir dose escalation (50mg BID) has limited data and is unlikely to overcome G118R-based resistance 1, 3

Methodological Strengths and Limitations

Strengths

• Comprehensive patient-level synthesis (n=103) with rigorous statistical analysis including Bonferroni and FDR correction demonstrates robust methodology
• Geographic diversity spanning Africa, South America, Europe, Middle East, and Asia enhances generalizability
• Network analysis revealing resistance constellation architecture provides mechanistic insights beyond simple mutation frequencies
• Sensitivity analysis (n=137) confirming primary findings strengthens conclusions

Limitations and Caveats

Selection bias considerations:

• Your cohort represents patients who failed therapy and underwent resistance testing, not all patients on dual NRTI + DTG 1
• True population-level resistance rates are likely lower than your 68.9% pan-INSTI figure, which applies only to those with detected DRMs 1, 4
• Adherence data were incompletely reported, limiting ability to distinguish resistance from non-adherence 1

Subtype analysis limitations:

• HIV-1 subtype was reported for only 82/103 patients (79.6%)
• The B/C overlap case counted in both groups may slightly inflate apparent differences
• CRF patterns remain heterogeneous with small sample sizes limiting conclusions

Temporal considerations:

• Studies predominantly post-2018 reflect recent DTG rollout but may not capture long-term resistance evolution 1
• Follow-up duration varied across studies, potentially missing late-emerging resistance patterns

Comparison with Existing Literature

Your findings align with but significantly extend prior systematic reviews:

Concordance with Rhee et al. (2019):

• Four signature resistance pathways (R263K, G118R, N155H, Q148HRK) confirmed 3
• G118R associated with >5-fold reduced susceptibility 3
• Q148 + G140/E138 combinations confer highest resistance levels 3

Novel contributions beyond prior reviews:

• First large-scale demonstration of G118R predominance over R263K in pooled real-world data 2
• Quantification of subtype-specific resistance patterns with statistical significance 2
• Network analysis revealing mutual exclusivity between R263K and G118R pathways 2
• Documentation of 68.9% pan-INSTI resistance rate among those with emergent DRMs 2, 3

Concordance with DTG RESIST collaborative analysis:

• INSTI DRMs detected in 14% of viraemic patients on DTG-based ART 4
• NRTI resistance substantially increased risk of dolutegravir resistance 4
• Your higher resistance rates likely reflect focus on dual NRTI + DTG rather than triple therapy 4

Geographic and Public Health Implications

For sub-Saharan Africa:

• Mozambique and Tanzania contributions (36.8% of your cohort) provide critical data from high-burden settings 2
• G118R predominance in subtype C populations threatens DTG-based first-line therapy sustainability 1, 2
• Limited access to resistance testing and novel salvage agents compounds the pan-INSTI resistance problem 1

For high-income settings:

• European and North American data show R263K predominance in subtype B, suggesting lower immediate risk 2
• However, 68.9% pan-INSTI rate still eliminates INSTI class for salvage in affected individuals 3

Recommendations for Clinical Practice

Baseline resistance testing:

• Perform genotypic resistance testing before initiating dual NRTI + DTG in treatment-experienced patients 1, 5
• In resource-limited settings, prioritize resistance testing for patients with prior NRTI exposure or viremia >500,000 copies/mL 5

Monitoring strategy:

• Viral load at 1 month, then every 3 months for first year on dual NRTI + DTG 1
• In subtype C populations, consider more frequent monitoring given G118R risk 2
• Any confirmed viremia warrants immediate resistance testing 1

Treatment selection:

• Avoid dual NRTI + DTG in patients with documented NRTI resistance unless no alternatives exist 1, 4
• If dual therapy is necessary with NRTI resistance, use DTG/3TC rather than DTG + TDF/FTC, as 3TC retains activity against M184V 1
• Consider triple therapy with DTG + 2 NRTIs + boosted PI in high-risk patients 1

Salvage therapy:

• For emergent G118R or Q148-based resistance, use lenacapavir-based regimens with novel agents 1
• Continue NRTIs despite resistance for partial activity 1
• Avoid switching between INSTIs in the presence of major DRMs 1, 3

Research Gaps Identified

Your review highlights critical knowledge gaps:

• Longitudinal studies tracking resistance evolution from R263K to G118R pathways are needed
• Pharmacokinetic studies examining whether suboptimal DTG levels contribute to G118R selection in subtype C
• Clinical trials of novel agents specifically in patients with G118R-mediated pan-INSTI resistance
• Cost-effectiveness analyses of baseline resistance testing versus empiric triple therapy in resource-limited settings