Dolutegravir seemed to be a promising maintenance monotherapy for people living with HIV, but the development of resistance mutations in testing strikes it from the list.
For patients who take antiretroviral drugs after being diagnosed with HIV, getting viral levels under control is the first step. The next step is keeping viral levels suppressed indefinitely via maintenance therapy. Figuring out which medications provide the best chance of achieving ongoing viral suppression while causing the fewest side effects is, therefore, of paramount importance.
Based on the results of an earlier small retrospective observational study, which suggested that dolutegravir’s high barrier to drug resistance—along with its once-a-day dosing schedule and lack of impact on blood lipid levels—might make it a good choice for a maintenance monotherapy, researchers from the Netherlands conducted their own trial to confirm whether this was true.
They recruited 104 subjects living with HIV who had already been treated with antiretroviral therapy (ART); all were virologically-suppressed, with RNA counts of less than 50 copies per mL and CD4 counts that had never dropped below 200. Fifty-one patients were assigned to immediately switch from combination ART to dolutegravir, and 53 patients switched to dolutegravir after 24 weeks of continuing on their regimen of combination ART. One goal of the study was to see how many patients had RNA viral loads of less than 200 copies per mL at the end of 24 weeks, which would signify adequate viral suppression. The patients were assessed again at 48 weeks.
During the study, one of the subjects who had immediately switched to dolutegravir had to drop out due to sleep disturbances. Of the subjects who continued taking combination ART for 24 weeks, six left the study before the 24 weeks were up for various reasons, including noncompliance and physicians’ recommendations. At 24 weeks, the 47 remaining subjects switched from combination ART to dolutegravir, with one subject subsequently dropping out because of sleep disturbances and one leaving the trial due to headaches.
The researchers found that at 24 weeks, dolutegravir was not inferior to combination ART when it came to viral suppression. Only one patient out of the 50 subjects who switched to dolutegravir immediately had RNA viral loads of 200 copies per mL or higher. None of the patients who delayed switching to dolutegravir had RNA viral loads at that level. However, the scientists concluded that they cannot recommend dolutegravir as a maintenance drug.
“Despite these promising results, virological failure was observed in seven additional patients after week 24, which led to virological suppression in 92% of patients at the time of study discontinuation,” the authors wrote in the study, which was published in The Lancet. “This result was statistically inferior to the 98% suppression rate observed in patients in the concurrent control group.”
The authors noted that all 8 patients who failed to achieve viral suppression on dolutegravir did achieve it once they returned to a regimen of combination ART, although that alone did not mean dolutegravir was an inappropriate choice for maintenance therapy. Upon sequencing the virus in six study subjects, the team discovered that mutations associated with medication resistance had arisen.
“Given the detection of resistance mutations in the integrase gene of more than two patients on dolutegravir monotherapy in our study, with the potential for cross resistance to other available and future integrase inhibitors, one of the stopping rules was met and the study was terminated,” they wrote.
The researchers’ conclusion? Dolutegravir is not an appropriate choice for maintenance monotherapy, a sentiment shared by Janine M. Trevillyan, MBBS, and Jennifer F. Hoy, MBBS, FRACP, Australian scientists who provided additional commentary in The Lancet. “The focus must now switch to the more promising dual-therapy options (such as dolutegravir and lamivudine or rilpivirine), or which large, randomised trials are underway,” they wrote.
Laurie Saloman, MS, is a health writer with more than 20 years of experience working for both consumer and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.