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Second-Line DTG Noninferior to DRV/r in African NADIA Trial
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Dolutegravir (DTG) plus two nucleos(t)ides (NRTIs) proved virologically noninferior to darunavir/ritonavir (DRV/r) plus NRTIs as second-line therapy through 48 weeks in a randomized African trial that used population monitoring typical of the public-health approach to HIV care [1]. The findings support World Health Organization (WHO) guidance to use the integrase inhibitor DTG in second-line regimens. A few cases of high-level resistance to DTG did arise during the trial.
Many resource-poor regions use the WHO approach to antiretroviral therapy (ART), which relies on standard first- and second-line regimens and simplified monitoring using sparse viral load and safety testing-and no resistance testing. After failure of a first-line nonnucleoside (NNRTI) regimen, the WHO recommends DTG plus two NRTIs, but that advice rests on a single randomized controlled trial that used resistance testing to pick NRTIs, excluded people with no predicted active NRTIs, and monitored participants with frequent viral load tests. Researchers mounted the NADIA trial to see if DTG would stand up as a reliable second-line cornerstone in regions using the public-health approach to ART.
NADIA enrolled people in whom an NNRTI plus emtricitabine (FTC) and tenofovir (TDF) or lamivudine (3TC) failed virologically (confirmed viral load at or above 1000 copies). A first randomization assigned participants to DTG or DRV/r. A second randomization assigned each group to TDF/3TC or zidovudine (ZDV)/3TC. People getting ZDV/3TC added TDF if they also had HBV infection. The primary outcome was proportion of participants with a viral load below 400 copies after 48 weeks by the FDA snapshot method.
Health workers checked CD4 count and viral load at weeks 24 and 48 and gave intensive adherence counseling to people with a viral load at or above 1000 copies-and then another viral load 12 weeks after counseling. People with a confirmed viral load at or above 1000 got real-time resistance testing.
Researchers enrolled 464 people from July to December 2019 at 7 sites in Uganda, Kenya, and Zimbabwe. Participants kept more than 99% of scheduled visits, and follow-up time on the assigned regimen stood at 96%.
Among the 235 people assigned to DTG and 229 assigned to DRV, proportions of women were 59.6% and 62%, median age stood at 33 and 35, median CD4 count at 189 and 202, and median viral load at 4.5 and 4.4 log10 copies/mL (about 32,000 and 25,000 copies/mL). At the baseline visit about half in each treatment arm had the K65R/N mutation making HIV resistant to TDF, and 86% had the M184V/I mutation making HIV resistant to 3TC and FTC. About 60% of participants had intermediate or high-level resistance to TDF, about 18% to ZDV, and more than 90% to 3TC.
At week 48 similar high proportions in the DTG group (90.2%) and the DRV/r group (91.7%) had a viral load below 400 copies in the intention-to-treat analysis (difference -1.49%, 95% confidence interval -6.7% to 3.7%, P = 0.576). That result meant that a DTG regimen was virologically noninferior to a DRV/r regimen after 48 weeks of second-line therapy. At 48 weeks proportions with a viral load below 50 copies were also similar with DTG and DRV/r in an intention-to-treat analysis (80.9% and 79.5%, P = 0.710).
In each group 6% had a confirmed viral rebound above 1000 copies. Among the 14 people with a confirmed rebound above 1000 copies in the DTG group, 4 (29%) had one or more major DTG resistance mutations detected. No one with a 1000-or-over rebound in the DRV/r group had a major DRV or DTG resistance mutation detected.
Viral load outcomes were similar with DTG and DRV/r regardless of whether participants got randomized to ZDV or TDF. Nor did virologic results differ much in people who started second-line therapy with a viral load above 100,000 copies or with 0 or 1 predicted active NRTI. There was a nonsignificant trend to worse virologic response to DTG in people who began second-line therapy with a CD4 count below 200. DTG and DRV/r regimens performed similarly in women and men.
Only 1 person in each treatment arm left the study because of an adverse event, and fewer than a dozen in each group had a serious adverse event. No one assigned to DTG and 2 (0.9%) assigned to DRV/r had an estimated glomerular filtration rate drop below 60 mL/min.
The NADIA team believes the noninferiority of DTG to DRV/r as second-line therapy in a public-health setting supports WHO advice to use DTG for second-line treatment. Specifically, they argued that these findings endorse the safety of a "programmatic switch of patients from [efavirenz] to DTG in settings without pre-switch viral load and resistance testing." But the researchers cautioned that "cases of DTG high-level resistance can occur" with this strategy. They see a need for more data on the risk of accumulating resistance to integrase inhibitors with the public-health approach.
Reference
1. Paton N, Musaazi J, Kityo CM, et al. Nucleosides and darunavir/ dolutegravir in Africa (NADIA) trial: 48 wk primary outcome. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 94LB.
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