Should We Switch to INSTIs in Treatment-Experienced PWH in Latin America?

For people with HIV (PWH) experiencing first-line failure on a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen, WHO guidelines currently recommend switching to an integrase strand transfer inhibitor (INSTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART). Furthermore, the WHO suggests switching from a tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) backbone to zidovudine (ZDV)/3TC in this context. Use of tenofovir alafenamide (TAF) has been recommended by the WHO in the setting of osteoporosis or renal impairment only.

New data from the VISEND study presented at the 2022 Conference on Retroviruses and Opportunistic Infections (CROI) challenged elements of this guidance on second-line ART. In addition, data from the 2SD study provided evidence in support of switching from a PI–based regimen to an INSTI-based regimen in treatment-experienced patients with virologic suppression for the purpose of enhancing safety and tolerability. These 2 studies have relevance across Latin America, where boosted PI–based regimens are frequently prescribed as second-line ART after treatment failure, in accordance with WHO guidelines, or are continued in treatment-experienced patients who have virologic suppression.

Switch to INSTI After NNRTI Failure
Previous Week 48 data from the DAWNING and NADIA studies support the efficacy of an INSTI-based regimen as second-line ART. Furthermore, the NADIA study demonstrated that continuation of TDF/emtricitabine (FTC) or 3TC was noninferior to switching to ZDV/3TC.

At CROI 2022, Mulenga and colleagues presented 144-week data from the VISEND study in Zambia, an open-label noninferiority study that compared second-line dolutegravir (DTG)- vs boosted PI–based regimens with TDF/3TC or TAF/FTC vs ZDV/3TC as the backbone.

In VISEND, PWH failing first-line NNRTI-based therapy were divided according to their baseline HIV-1 RNA: those with HIV-1 RNA <1000 copies/mL were randomized to receive TDF/3TC/DTG or TAF/FTC/DTG, and those with HIV-1 RNA >1000 copies/mL were randomized to receive TDF/3TC/DTG, TAF/FTC/DTG, ZDV/3TC/lopinavir (LPV)/ritonavir (RTV), or ZDV/3TC/atazanavir (ATV)/RTV.

In those with lower HIV-1 RNA, outcomes were similar in both DTG-based regimens. In those with higher HIV-1 RNA, the percentage of patients attaining HIV-1 RNA <1000 copies/mL and <50 copies/mL was significantly lower in the group receiving LPV/RTV. Both the TDF/3TC/DTG or TAF/FTC/DTG groups were superior to the PI–based regimens with ZDV/3TC. Consistent with other trials, weight gain was more likely in the TAF arms, especially in women.

These results support the use of DTG with either TDF or TAF for PWH failing NNRTI-based first-line regimens. Of importance, they suggest that ZDV should no longer be used in the backbone. Because weight gain was more pronounced in the TAF groups, especially in women, therapy should be individualized with consideration for risk of obesity and other comorbidities.

Switch to INSTI After Boosted PI Success
Other trial results with implications for Latin America were from the open-label 2SD trial in Kenya, which evaluated switching to a DTG-based regimen vs continuation of a boosted PI–based regimen in treatment-experienced adults with virologic suppression.

In the intention-to-treat analysis at 48 weeks, Ombajo and colleagues reported no differences between the groups in the percentage of patients with HIV-1 RNA ≥50 copies/mL (the primary endpoint). In their secondary analysis, the percentage of patients with HIV-1 RNA >200 copies/mL in the DTG group was 0.3% vs 1% in the boosted PI–based group. These data established the noninferior efficacy of the DTG-based regimen using a 4% noninferiority margin. When considering safety parameters, lipid profiles were significantly more favorable in the DTG group vs the boosted PI–based group.

Data from the VISEND and 2SD studies are important for all low- and middle-income countries, including many countries in Latin America. Although healthcare professionals in Latin America consider an INSTI-based regimen—typically DTG—to be the preferred first-line ART, many still preferentially prescribe boosted PI–based regimens as second-line therapy. These studies demonstrate that DTG may be preferred as a second-line treatment and used as a switch strategy in treatment-experienced patients with viral suppression receiving a boosted PI–based regimen.

Your Thoughts?
Will the results of these studies on switching to INSTI-based regimens as second-line therapy influence your clinical practice in Latin America? Join the discussion 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.