{"id":39678,"date":"2021-01-22T07:39:30","date_gmt":"2021-01-22T07:39:30","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=39678"},"modified":"2021-02-03T15:11:47","modified_gmt":"2021-02-03T15:11:47","slug":"baseline-nnrti-resistance-linked-to-poorer-response-to-first-line-dolutegravir-96-week-results-of-advance-study","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/39678","title":{"rendered":"Baseline NNRTI resistance linked to poorer response to first-line dolutegravir in the ADVANCE study\u00a0\u00a0 \u00a0\u00a0\u00a0"},"content":{"rendered":"
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Polly Clayden, HIV i-Base<\/span><\/strong><\/p>\n<\/div>\n

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Participants with pretreatment NNRTI resistance, receiving dolutegravir (DTG) in ADVANCE, had lower rates of viral suppression at 96 weeks than those without \u2013 according to findings reported in the 1 December issue of Nature Communications. [1]<\/span><\/b><\/p>\n<\/div>\n

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ADVANCE is an ongoing, three arm, 192-week, phase 3 study, comparing first-line ART with: tenofovir alafenamide (TAF)\/emtricitabine (FTC) + DTG, tenofovir disoproxil fumarate (TDF)\/FTC + DTG or TDF\/FTC\/efavirenz (EFV). Week 96 data were presented this year. [2]<\/span><\/p>\n<\/div>\n

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The resistance analyses were conducted with the hypothesis<\/span> that <\/span>pre-treatment NNRTI resistance significantly affects efficacy of EFV-containing regimens but has a negligible effect on outcomes for those starting DTG-based therapy.<\/span><\/p>\n<\/div>\n

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Of 1053 participants enrolled in ADVANCE, <\/span>991 (94%)\u00a0consented for specimen storage and had pretreatment plasma available; 874 (83%) had successful sequencing. <\/span><\/p>\n<\/div>\n

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Among participants included in the resistance analyses, 289 (33%) were randomised to the EFV and 585 (67%) to the DTG arms. All had completed week 96 of the study at the time of the analyses. Participants starting DTG-based regimens had a higher prevalence of <\/span>pretreatment drug resistance than those starting EFV-based regimens: 16.5 vs 7.4%,\u00a0p<\u20090.001. Otherwise, there were no clinical or demographic differences between the two groups.<\/span><\/p>\n<\/div>\n

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The investigators found 14% (122\/874) of participants with at least one WHO-defined pretreatment drug resistant mutation. Most of the resistance was to NNRTIs, with over 98% (120\/122) of participants with pretreatment resistance having at least one NNRTI mutation.<\/p>\n<\/div>\n

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K103N was the most common NNRTI mutation (9%, 81\/874). Only 2% (20) of participants had a NRTI mutation. M184V was the most frequent (1%, 12 participants) followed by K65R (1%, 8 participants). Two per cent (18 participants) had at least one NRTI mutation and one NNRTI mutation.<\/p>\n<\/div>\n

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Rates of virologic suppression were significantly lower overall in participants with pretreatment drug resistance than those without: respectively, 65% (73\/112) vs 85% (605\/713), p<\u20090.001.<\/span><\/p>\n<\/div>\n

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This was similar for those starting EFV- or DTG-based ART: respectively, <\/span>60% (12\/20) vs 86% (214\/248),\u00a0p\u2009=\u20090.002, and 66% (61\/92) vs 84% (391\/465), p<\u20090.001.<\/span><\/p>\n<\/div>\n

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In multivariate analysis, adjusted for demographics, clinical factors and adherence, pretreatment drug resistance was a strong predictor of virologic success: AOR 0.38 (95% CI 0.21 to 0.61). <\/span><\/p>\n<\/div>\n

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Results were similar when the investigators assessed persistent virologic failure (defined as two consecutive viral loads >200 copies\/mL): respectively, 85% (73\/86) vs 94% (428\/453),\u00a0<\/span>p=\u20090.001 and 68% (13\/19) vs 93% (217\/233),\u00a0<\/span>p\u2009<\u20090.001 for DTG and EFV-based ART.<\/span><\/p>\n<\/div>\n

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By contrast, pretreatment drug resistance only had an effect on early virologic response for participants receiving EFV-based but not DTG-based ART. At week 12, the drop in viral load was greater for those without pretreatment drug resistance in the EFV arm but not in the DTG arms: respectively 1.89 vs 2.61 log<\/span>10<\/span>\u00a0<\/span><\/span>copies\/mL,\u00a0<\/span>p<\u20090.001, and 2.76 vs 2.68 log<\/span>10<\/span>\u00a0<\/span><\/span>copies\/mL,\u00a0<\/span>p<\u20090.43\u00a0(<\/span>p=<\/i>0.001 for interaction between arms).<\/span><\/p>\n<\/div>\n

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The investigators wrote that \u201c\u2026the finding that NNRTI resistance appears to ultimately predict treatment failure among individuals initiating DTG-based ART in LMIC was unexpected, and to our knowledge not previously reported in the literature\u201d.<\/span><\/p>\n<\/div>\n

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They noted that<\/span> integrase resistance mutations were not assessed in this study but are generally believed to be rare (<1%) in this region. <\/span><\/p>\n<\/div>\n

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They speculated that one explanation for the lack of long-term suppression in participants receiving DTG-based ART might be behavioral \u2013 pre-existing EFV mutations could be a linked to earlier undisclosed ART exposure. Previous ART exposure has been associated with treatment failure and predicts virologic failure, even after controlling for pretreatment drug resistance and adherence. <\/span><\/p>\n<\/div>\n

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comment<\/span><\/h3>\n<\/div>\n
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The finding that NNRTI resistance is associated with a reduction in efficacy of DTG-based ART has multiple public health implications. <\/span><\/strong><\/p>\n<\/div>\n

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It means that viral load monitoring remains a priority with DTG-based regimens.<\/span><\/strong><\/p>\n<\/div>\n

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Second- and third-line options will also still be needed and integrase inhibitor resistance testing should be considered.<\/span><\/strong><\/p>\n<\/div>\n

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However, the authors also recommend that these findings need to be validated. Future analyses should also:<\/span><\/strong><\/p>\n<\/div>\n

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