HIV Monotherapy Shows Substantial Risk of Harm

In an effort to make HIV treatment easier for patients, a study recently compared the safety and efficacy of dolutegravir to that of combination antiretroviral therapy (ART).

Researchers hypothesized that fewer drugs for maintenance may reduce the incidence of treatment-related adverse events, as well as reducing costs and pill burden. Combination ART regimens were deemed effective. However, increased virologic failure and drug resistance following dolutegravir monotherapy led researchers to recommend against its use.

DOMONO, an open-label, phase 2 trial, assessed the non-inferiority of dolutegravir monotherapy to combination ART for maintenance of virologic suppression in patients with HIV-1 infection who had been treated successfully with combination ART. Upon enrollment, a group of 51 patients switched immediately to monotherapy with dolutegravir. A second group of 53 patients were switched after a 24 week delay, during which they received continued treatment with combination ART.

After 24 weeks, 2% of the patients who immediately switched to monotherapy had plasma HIV RNA loads of 200 copies/mL or higher (2% difference; 95% CI, —5 to 12). No difference was observed in the delayed switch group.

At week 48, virologic failure occurred in 8% of the 95 patients who were still receiving dolutegravir monotherapy — 6 were from the group that switched immediately, and 2 from the group who delayed the switch.

Three of the patients who had virologic failure also showed resistance mutation in the integrase gene, leading the research team to discontinue the study early. At the study’s outset, the team decided to stop the study early if more than 2 patients exhibited resistance, and if more than 20 patients had monotherapy failure.

The research team wrote: “Because all 8 patients with virologic failure achieved resuppression of the plasma viral load soon after reinitiation of combination ART, this observation alone would not contraindicate dolutegravir monotherapy. However, the results of integrase sequencing at the time of virologic 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.”

“There is interest in simplification of combination ART for use in maintenance therapy, with no cure for HIV on the horizon," research fellow Janine M. Trevillyan, MBBS, FRACP, and Jennifer F. Hoy, MD, Professor of Infectious Diseases and Director of HIV Medicine at Alfred Hospital and Monash University, in Melbourne, Australia, wrote in a Lancet commentary published October 26. "Treatment with combination ART is lifelong and leads to a near-normal life expectancy in most patients. To maintain durable virologil suppression, combination ART needs to be taken reliably. Pill burden, toxicity, and cost have stimulated investigation of simpler maintenance regimens.”

“With substantial risk of harm and minimal evidence of benefit, little justification exists for ongoing investigation of monotherapy strategies,” Trevillyan and Hoy continued. “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.”

The study, “Dolutegravir as maintenance monotherapy for HIV: a phase 2, randomized non-inferiority trial,” was published in The Lancet.

This article was originally published by MD Magazine.