Background:
Most countries recommend tenofovir-lamivudine-dolutegravir (TLD) for individuals starting antiretroviral therapy (ART) or switching from suppressive 1st-line NNRTI- or 2nd-line PI-based ART but country guidelines have been more variable about using TLD for those with unsuppressed (plasma HIV-1 RNA>1000 c/ml) viral load (VL) on ART. We report virologic and resistance outcomes for unsuppressed individuals switching to TLD in the A5381 prospective cohort study.
Methods:
Participants were adults or adolescents aged >10y with VL>1000 c/ml switching from 1st-line NNRTI-based (Cohort 1) or 2nd-line PI-based (Cohort 2) ART. Primary endpoints were proportion with VL≤1000 c/ml at 6 months (m) after switch among those still on TLD and proportion with new DTG resistance mutations (baseline and 6m samples were sequenced for those with VL>1000 c/ml at 6m). A case-control study (unsuppressed vs suppressed) evaluated tenofovir diphosphate (TFV-DP) concentrations in dried blood spots.
Results:
From Dec2019 to Sep2022, 44 participants were enrolled into Cohort 1 (77% female, median age 33y) and 173 were enrolled into Cohort 2 (57% female, median age 41y) at 13 sites in Haiti and Africa. In Cohort 1, median VL was 4.0 log10 c/ml, CD4 count was 306 cells/mm3, time on ART was 5.5y. In Cohort 2, median VL was 4.2 log10 c/ml, CD4 count was 262 cells/mm3, time on ART was 5.4y. Of 42 participants in Cohort 1 on TLD with VL results at 6m, 88% had VL≤1000 c/ml (95% CI: 74%, 96%) and 83% had VL≤200 c/ml (CI: 69%, 93%); 0/42 (0%) had new DTG mutations (CI: 0%, 8%). Of 165 participants in Cohort 2 on TLD with VL results at 6m, 72% had VL≤1000 c/ml (CI: 64%, 78%) and 67% had VL≤200 c/ml (CI: 59%, 74%); 2/163 (1.2%, CI: 0%, 4%) had new DTG mutations (G118R and R263K). Viral suppression declined in both groups over 24m (Table). TFV-DP concentrations were lower among participants with VL >1000 vs ≤1000 at 6m: median 127 vs 663 fmol/punch in Cohort 1 (p=0.19; n=5 pairs) and 169 vs 1029 fmol/punch in Cohort 2 (p<0.001
Conclusions:
Participants with unsuppressed VL who switched to TLD had improved but suboptimal virologic suppression (<90%) that did not improve over time. Viral suppression was lower in participants switching from 2nd-line PI-based regimens than from failing 1st-line NNRTI-based regimens. Infrequent emergence of DTG mutations and lower TFV-DP concentrations in unsuppressed vs suppressed suggest that incomplete adherence to TLD was the major mechanism for failure to suppress viremia.
