Is dolutegravir monotherapy safe as maintenance for HIV patients?
Simplification from combination antiretroviral therapy (cART) to dolutegravir monotherapy as maintenance treatment was noninferior to continuing therapy with cART, at least in patients who initiated cART during primary HIV infection and had achieved suppressed viral load for ≥48 weeks, suggests a study presented at IAC 2018.
Previously, many believed that “dolutegravir monotherapy is dead,” according to Dr Dominique Braun from the University of Zurich, Zurich, Switzerland, who pointed out that dolutegravir monotherapy was not recommended due to reports of virological failures with development of resistance to the drug in two randomized trials. [J Antimicrob Chemother 2018;doi:10.1093/jac/dky093; Lancet HIV 2017;4:e547-e554]
However, the concept of monotherapy has not been tested in patients who initiated cART during primary HIV infection (ie, within 6 months after infection), in whom HIV-1 reservoir size was shown to be smaller than those who started cART during chronic infection. The investigators thus set out to test if a smaller HIV-1 reservoir size translates into sustained viral suppression after simplification to dolutegravir monotherapy.
The open-label, noninferiority trial included 101 patients who initiated cART during primary HIV infection and had achieved viral suppression (HIV-1 RNA <50 copies/mL) for at least 48 weeks. The participants were randomized 2:1 to simplification to dolutegravir 50 mg once daily or to continuation with cART. [IAC 2018, abstract TUAB0102]
At week 48, all patients in the monotherapy as well as the cART arms had achieved virological response (difference, 0 percent, 95 percent confidence interval [CI], -1 to 0.047) in the per-protocol analysis, thus meeting the prespecified noninferiority criteria.
“Future simplification studies should use a stratification according to time of HIV infection until start of first cART,” said Braun.
He pointed out that although one patient in the dolutegravir monotherapy arm experienced virological failure at 36 weeks in the intent-to-treat population, the patient was found to be in chronic infection when initiating cART (thus violating the inclusion criteria for the study) and was therefore excluded from the per-protocol analysis. Viral load was resuppressed on cART.
In addition, both treatment arms showed comparable slight decay of HIV-1 DNA reservoir and no HIV-1 RNA was detected in all patients.
In terms of safety, eight serious adverse events (AEs) were reported overall (8.8 percent and 6.1 percent in monotherapy and cART arms, respectively), but none was related to the study drugs. Commonly reported AEs that were probably or possibly related to the drug included elevated liver enzyme and creatinine levels, nausea, and fatigue.
A different picture
Another separate noninferiority study, MONCAY, with a different design found that although dolutegravir monotherapy was noninferior to cART at week 24, there was a substantial risk of emerging resistance mutations to integrase inhibitor (INI). [IAC 2018, abstract TUAB0103]
Subjects in the MONCAY study were 78 patients who had been stable on a cART of dolutegravir/abacavir/lamivudine with plasma HIV-RNA of <50 copies/mL for >12 months, nadir CD4 >100/mm3, no AIDS event, and no resistance to or failure on any INI. The patients were randomized 1:1 to continue cART or to simplify to dolutegravir monotherapy.
Dolutegravir monotherapy was noninferior to cART, with 94 percent vs 96 percent patients in each respective arm achieving the primary endpoint of HIV-RNA <50 copies/mL at week 24. However, two patients in the monotherapy arm had virological failure by week 24 and five more cases occurred with emergence of resistance mutation to INI during further follow-up till week 48, while none occurred in the cART arm throughout the study.
“Although noninferior to cART at week 24, dolutegravir monotherapy was not a valid option to maintain virological suppression over time in HIV-1-infected patients on a successful cART therapy and favoured emergence of INI resistance,” concluded Dr Laurent Hocquelox from CHR d'Orléans in Orléans, France.
“[Our study] confirm that dolutegravir monotherapy as a maintenance strategy is not safe over time and should therefore not be used in people living with HIV.”
Noting the unpredictability of viral rebound with monotherapy in the MONCAY study, a member of the audience pointed out that in the context of a shift towards less frequent monitoring of viral load, simplification to monotherapy would put patients at risk of developing cross-resistance as well as transmitting HIV to their partners.