Dolutegravir monotherapy leads to resistance
Dolutegravir monotherapy recently met its primary endpoint of noninferiority in a phase 2 trial comparing its safety and efficacy with combination ART. In the following weeks, however, monotherapy was associated with an increase in virological failure and drug resistance, leading researchers to recommend against its use.
Although combination ART regimens are effective, there is a need to simplify treatment, according to Ingeborg Wijting, MD, of the department of internal medicine and infectious diseases at Erasmus MC University Medical Center, the Netherlands, and colleagues. The researchers suggested in The Lancet HIV that maintenance therapy with fewer drugs may reduce the number of treatment-related adverse events, pill burden and costs.
The researchers conducted an open-label, phase 2 noninferiority trial, DOMONO, to assess the outcomes of virally suppressed adults at two medical centers in the Netherlands who switched from combination ART to monotherapy with dolutegravir.
“Various factors make dolutegravir a suitable candidate for maintenance monotherapy: the development of resistance is rare in patients previously untreated with integrase inhibitors; the risk of drug interactions is low; and the drug has good tolerability, a once-daily dosing scheduling, a small pill size, and a neutral effect on serum lipids,” the researchers wrote.
Participants were switched to a once-daily 50-mg dose of dolutegravir monotherapy immediately after enrollment (n = 51) or after 24 weeks of continuing combination ART (n = 53). The primary endpoint was the proportion of patients with an HIV RNA viral load less than 200 copies/mL at week 24. The researchers established a noninferiority margin of 12%.
At 24 weeks, 2% of patients who immediately switched to monotherapy and no patients in the delayed switch group had plasma HIV RNA loads of 200 copies/mL or higher (2% difference; 95% CI, –5 to 12). By week 48, 8% of the 95 patients who remained on dolutegravir monotherapy had virological failure, including six in the immediate switch group and two in the delayed switch group. In addition, resistance mutations in the integrase gene were detected in three patients with virological failure. As a result, the researchers discontinued the study early in accordance with a predefined stopping rule that required premature discontinuation if resistance was found in more than two patients and failure of monotherapy occurred in more than 20 patients.
“Because all eight patients with virological failure achieved resuppression of the plasma viral load soon after reinitiation of combination ART, this observation alone would not contraindicate dolutegravir monotherapy,” the researchers wrote. “However, the results of integrase sequencing at the time of virological failure clearly showed that dolutegravir monotherapy cannot replace combination ART, even in patients with a CD4 nadir above 200 cells per L and an HIV RNA zenith of less than 100,000 copies per mL.”
In a related editorial, research fellow Janine M. Trevillyan, MBBS, FRACP, and Jennifer F. Hoy, MD, professor of infectious diseases and director of HIV Medicine at the Alfred Hospital and Monash University, Melbourne, Australia, said there should be “wholehearted agreement” that dolutegravir should not be administered to patients as maintenance monotherapy.
“With substantial risk of harm and minimal evidence of benefit, little justification exists for ongoing investigation of monotherapy strategies,” they wrote. “The focus must now switch to the more promising dual-therapy options (such as dolutegravir and lamivudine or rilpivirine), for which large, randomized trials are underway.” – by Stephanie Viguers
Disclosures: Hoy reports receiving fees on behalf of her institution from AbbVie, Gilead Sciences, Merck and ViiV Healthcare. Wijting reports receiving personal fees from Gilead Sciences. Please see the study for a list of all other authors’ relevant financial disclosures.