Dolutegravir Monotherapy for HIV No Longer Recommended: Study

Dolutegravir monotherapy should no longer be used as HIV maintenance therapy, according to Bart J.A. Rijnders, MD, PhD, and Casper Rokx, MD, PhD, both from Erasmus Medical Center, Rotterdam, the Netherlands.

After dolutegravir-based combination antiretroviral therapy (cART) was approved for treatment of HIV-1 in the United States in 2013, and in Europe in 2014, evaluation of dolutegravir maintenance monotherapy initially made sense, say Drs. Rijnders and Rokx in a recent article published online in the journal Clinical Infectious Diseases.

But knowledge of the effectiveness of dolutegravir antiretroviral monotherapy for HIV has significantly evolved in recent years. Despite promising early results, subsequent prospective clinical trials showed that dolutegravir monotherapy is inferior to combination antiretroviral therapy for long-term HIV treatment. Additionally, its use is associated with viral rebounds and emergences of integrase resistance.

Drs. Rijnders and Rokx highlight data from the recently published French randomized MONCAY study. Investigators on this study aimed to determine whether a switch to dolutegravir monotherapy would be noninferior to continuing dolutegravir-based triple-therapy in maintaining virological suppression.

At 24 weeks, the investigators found that dolutegravir monotherapy was noninferior compared with triple-therapy, with 94% of the participants receiving monotherapy having a viral load below 50 c/ml compared with 96% of those receiving triple therapy. Virological rebound above 50 c/ml occurred in 2 patients receiving monotherapy, and in none of those receiving triple-therapy.

However, between weeks 24 and 48 of follow-up, 5 more cases of virologic rebound occurred in patients receiving dolutegravir monotherapy. And 2 of these cases involved participants developing new integrase inhibitor resistance mutations.

“Because the risk of virological failure with resistance increases overtime, we recommend avoiding dolutegravir monotherapy as a maintenance strategy among people living with chronic HIV infection,” the investigators emphasized.

And, according to Drs. Rijnders and Rokx, further analysis of data from the MONCAY study, and also from the DOMONO study, has shown that the risk of viral rebound during monotherapy was greater in patients who had a lower CD4 nadirs and a higher HIV-DNA. These 2 factors indicate a more advanced disease state with a larger HIV reservoir, they said. This suggests that maintenance dolutegravir monotherapy may have a role in treating a subgroup of HIV-1 patients with a smaller, less genetically diverse HIV reservoir, they added.

Drs. Rijnders and Rokx also discussed the recently published Swiss randomized EARLY SIMPLIFIED study. Investigators on this study aimed to determine whether dolutegravir monotherapy would maintain viral suppression better in people who had begun treatment during the acute phase of their HIV infection, and whether a smaller HIV reservoir and reduced viral diversity would lower the risk of viral rebound when antiretroviral treatment was switched to monotherapy.

The investigators focused on simplification of HIV therapy among patients who had been successfully treated with combination antiretroviral therapy for at least 48 weeks since primary HIV-1 infection, and who were then randomized to DTG monotherapy.

A total of 101 participants were randomized to either continue 3-drug combination antiretroviral therapy (n = 33) or switch to dolutegravir monotherapy (n = 68). The results showed that dolutegravir monotherapy was inferior to combination antiretroviral therapy, with 100% of participants in both study arms maintaining viral suppression.

The investigators noted that success of simplification strategies using dolutegravir monotherapy was likely determined by early start of treatment with subsequent low latent HIV-1 reservoir size, low viral diversity, and low immune activation. “It suggests that trials evaluating simplification strategies should stratify between patients first treated during primary and chronic infection,” they stressed.

“Where do we go from here with dolutegravir or other future monotherapy studies?,” asked Drs. Rijnders and Rokx.

Although they emphasized that dolutegravir as HIV maintenance monotherapy should no longer be used, they noted that 1 exception may be in a specific subset of patients, as studied in EARLY-SIMPLIFIED, or in patients with favorable reservoir and host characteristics that we must first gain a better understanding of.

“We therefore think that studies on monotherapy remain acceptable from an ethical point of view provided that the drug has a (very) high genetic barrier against the development of resistance and that a stringent set of common-sense rules are followed to protect the patient’s safety,” they concluded.