My Take on Dolutegravir Use in Patients With Virologic Failure: Data From CROI 2022

As of 2020, 73% of the total number of people with HIV (PWH) worldwide have received ART. In many regions of the world, the most common first-line ART regimen for the past 2 decades was 2 NRTIs combined with 1 non-nucleoside reverse-transcriptase inhibitor, and the most common ART regimen used after failure of the first-line regimen was 2 NRTIs plus an RTV-boosted protease inhibitor (PI). In many developing countries, the boosted PI until recently has been LPV/RTV, a PI whose use is coupled with both lipid and gastrointestinal adverse events. The integrase strand transfer inhibitor (INSTI) DTG is being investigated as an alternative to a boosted PI in second-line ART. 

DAWNING Study: DTG in Second-line ART
Many clinical trials have shown that DTG has noninferior or superior antiretroviral efficacy vs various comparators, a high genetic barrier to resistance, and a favorable safety profile when used as part of an initial ART combination. The DAWNING study investigated DTG in patients with virologic failure on first-line ART. In this study, the DTG regimen demonstrated superior efficacy to the boosted PI regimen with few grade 2-4 adverse events. In addition, there was higher efficacy with DTG in people with baseline resistance, including M184V/I, K65R, and/or ≥1 thymidine analogue mutation. Based on these data and real-world use, the WHO guidelines on ART now recommend DTG-based ART for both initial ART and second-line therapy in people who received other types of first-line ART. 

VISEND: CROI 2022 Data on DTG in People With Virologic Failure on First-line ART
Data from the 2022 Conference on Retroviruses and Opportunistic Infections (CROI) add to what we know about the use of DTG as second-line therapy. The VISEND trial in Zambia enrolled PWH receiving first-line lamivudine (3TC)/tenofovir disoproxil fumarate (TDF) plus either efavirenz or nevirapine who had HIV-1 RNA ≥1000 copies/mL (arm B; a separate component of the trial enrolled patients with HIV-1 RNA <1000 copies/mL to compare switch to DTG plus 3TC/TDF vs DTG plus emtricitabine [FTC]/tenofovir alafenamide [TAF]). Participants were randomized to receive either DTG combined with 3TC/TDF or FTC/TAF, or a boosted PI regimen of LPV/RTV or ATV/RTV plus 3TC/TDF; therefore, each group had essentially recycled the NRTI pair 3TC/TDF. At Week 48, 83% of participants in the DTG plus 3TC/TDF arm and 86% of those in the DTG plus FTC/TAF arm achieved viral suppression vs 76% in the combined PI-based regimen groups. The study findings suggest that DTG-based second-line ART had superior efficacy and tolerability, even when used in combination with recycled NRTIs. In addition, DTG has other advantages, such as once-daily dosing with no food restrictions, which can help with adherence and reduce the risk of future regimen failure.

DTG and Weight Gain
However, some clinical trials have demonstrated that INSTIs may cause abnormal weight gain in PWH, particularly when coupled with the NRTI TAF, and thereby may increase the risk for metabolic complications. The VISEND trial also demonstrated higher weight gain in women receiving DTG-based second-line ART that included TAF vs those treated with a PI-based regimen or DTG in combination with 3TC/TDF. The latest ART guidelines from the WHO, European AIDS Clinical Society, and US Department of Health and Human Services all recommend that PWH should be assessed for BMI at the time of starting ART and during annual follow-ups. 

Regimens containing DTG are recommended as the preferred option in both first-line and second-line regimens by the WHO guidelines, which are aimed at achieving greater public health benefits through optimizing drug options and quality of life for PWH. In Asia, most countries ascribe to WHO recommendations and have included DTG in their national guidelines. At the end of 2021, China instituted a new formulary of free ART that includes DTG as the preferred anchor drug in second-line therapy. We hope to contribute more real-world data to further illustrate the role of DTG in second-line ART.

Your Thoughts?
What is your practice regarding the use of INSTIs in second-line ART? Join the conversation by posting a comment.

For more details on this and other key HIV issues from CROI 2022, review more CCO Conference Coverage, including Capsule Summary slidesets and other ClinicalThought commentaries highlighting US and global perspectives.