Intermittent dosing of dual HIV therapy for HIV disappoints in DUETTO trial

Four-day-a-week dosing of dual therapy for HIV performs similarly to daily doses in terms of sustaining viral suppression in the DUETTO trial. However, virological failure (VF) and drug resistance rates were higher with the 4-day/week dosing regimen.

“Despite the high virological success [>94 percent] with dual therapy, taking the medication 4 days/week failed to achieve noninferiority in terms of VF compared with daily use,” said the researchers.

In the era of effective antiretroviral therapy, experts are exploring new strategies to safely reduce the number of medication doses while maintaining virological control. Several attempts have also been made to test different drug-sparing regimens to reduce cost and potential drug-related toxicities.

4-day/week dosing of triple therapy

In the previous QUATUOR study, the 4-consecutive-days-on and 3-days-off dosing strategy was noninferior to the standard 7-day regimen of triple therapy over 48 weeks in adults with HIV-1.

The rate of treatment failure did not differ according to the antiretroviral drug class, nor was there a difference in the frequency of viral ‘blips’ above 50. [Lancet HIV 2022;9:e79-90]

Despite the promising findings, there have been some concerns about the durability of the 4-day approach, given that drug resistance can emerge over time.

4-day/week dosing of dual therapy

In the DUETTO trial, Dr Roland Landman of Hôpital Bichat, Paris, and his team sought to evaluate the efficacy and safety of maintenance dual therapy taken 4 days/week vs 7 days in 433 adults with controlled viral load (<50 c/mL) for >12 months, with no documented resistance to therapy. They were randomized 1:1 (n=219 to 4/7 days, n=214 to the 7-day regimen) and stratified according to their baseline dual therapy.

Among the participants, 65.6 percent were on dolutegravir plus lamivudine (DTG/3TC) and 33.7 percent were on dolutegravir plus rilpivirine (DTG/RPV). Only three (0.7 percent) were on darunavir/ritonavir plus 3TC (DRV/r+3TC).

The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population with VF at week 48, using the FDA snapshot approach, with a 5 percent noninferiority margin.

At week 48, VF was observed in 8 patients (3.7 percent) in the 4-day/week group and none in the 7-day group (0 percent; adjusted difference 3.7 percent, 95 percent confidence interval [CI], 1.2– 6.2). The per-protocol analysis yielded similar results.

Therapeutic success was obtained in 94.5 percent of patients in the 4-day/week group and 96.3 percent of those in the 7-day group, for an adjusted difference of  -1.8 percent.  Adverse events were similar between the two groups. The incidence of viral clips per 100 person-years was 12.6 in the 4-day/week group vs 4.2 in the 7-day group (p=0.0037).

Of the eight cases of VF, resistance mutations were detected in four participants at failure, two of whom had unexpected drug mutations in pro-viral RNA/DNA at baseline and one had a low plasma drug concentration.

In this relatively large trial, intermittent dosing of commonly used dual therapies for HIV failed to achieve noninferiority in terms of VF compared with daily doses.  Six (4.2 percent) of those on intermittent DTG/3TC experienced VF. Of those with resistance at failure, four had treatment-emergent resistance. Overall, the findings suggest that some commonly used dual therapies for HIV might be less forgiving of skipped and missed doses.