Dolutegravir monotherapy studies halted due to integrase resistance: dual therapy studies continue
Simon Collins, HIV i-Base
Several studies at CROI 2017 reported a similar conclusion: reducing ART to dolutegravir monotherapy should be stopped. However, dual therapy with dolutegravir can still be studied, especially with lamivudine.
Initial hopes that dolutegravir was sufficiently robust against developing drug resistance that might enable it to be used as monotherapy have not been upheld. Although the majority of people continue to maintain undetectable viral load, the risk of viral rebound is unpredictable and associated with drug resistance to integrase inhibitors. These risks are now recognised as being too serious for monotherapy to be used – either in research or clinical practice.
Dolutegravir monotherapy – no longer recommended
José Blanco from Hospital Clinic Barcelona reported on a combined analysis on 122 patients from three separate clinical cohorts – in Munich (n=52), Barcelona (n=44) and Montreal (n=26) – in an oral presentation at the start of CROI 2017. 
All participants were treatment-experienced patients with no history of integrase inhibitor resistance who switched to dolutegravir monotherapy. The analysis used a comparison cohort of 1082 patients from Barcelona (n=680) and Montreal (n=402) clinics of patients using dolutegravir as part of dual or triple drug ART.
Overall, virological failure in the monotherapy group was reported in 11/122 (9%; 95%CI: 6 to 18%), with incident genotypic integrase resistance detected in 7/11 patients. In comparison, virological faliure was reported in 64/1082 patients in the control group (6%; 95%CI: 5 to 7%). This resulted in an odds ratio (OR) for virological failure in the monotherapy group of 1.58 (95%CI: 0.73 to 3.13). However, none of the patients in the control group developed genotypic integrase mutations.
Details for the 11 patients (8 men, 3 women) in the monotherapy group with virological failure included median age 50 years (42 to 70), many had been HIV positive for more than 20 years (range 10 to 29) and median of 7 previous ART combinations (range 1 to 11) with history of mean 3 (range 0 to 8) previous virological failures. However, comparable data were not presented for either the whole monotherapy cohort or the control group.
In 5/11 (45%) dolutegravir was the first integrase inhibitor, 8/11 had been virologically suppressed for > 3 years, adherence was <95% in 4/11 cases and time from failure to resistance testing was a median of 5 weeks (IQR: 3 to 14).
Mutations detected for the 9/11 patients included different resistance pathways: 92Q/155H (n=1), 97A/155H (n=1), 155H/148R (n=1), 118R (n=2), 148K (n=1), 148H (n=2) and 148 R (n=1).
A late breaker poster from a Belgium study of dolutegravir reported a similar concern about drug resistance and has already switched all participants to triple therapy.
Ingeborg Wijting from the Erasmus University Medical Centre reported results from the DOMONO study that randomised 104 patients with viral suppression <50 copies/mL for >6 months to either switch to dolutegravir monotherapy or to stay on their three-drug ART for 24 weeks. If the monotherapy strategy performed well then all participants moved to dolutegravir monotherapy at 24 weeks. To overcome the lack of a 48-week control, a concurrent group of 152 patients on ART was also used for a post hoc analysis (non-randomised).
Entry criteria included no history of treatment failure, CD4 nadir >200 cells/mm3 and viral load zenith <100,000 copies/mL.
At baseline, median time on ART was 40 months and median CD4 nadir was 340 cells/mm3.
At week 24, dolutegravir monotherapy was non inferior to triple ART for the primary endpoint of viral load VL<200 copies/mL. Viral suppression was maintained in 49/50 monotherapy vs 53/53 in triple ART group (difference 2%, 95%CI: +12% to -5%), with no integrase resistance in the single case of viral failure.
Also at week 24, 46/53 participants initially randomised to triple ART, switched to monotherapy. Overall, of the 96 participants on dolutegravir monotherapy, 94/96 reached week 24. 92/94 had a VL<200 copies/mL, with no resistance in the two viral failures.
However, when 77/96 participants reached week 48, viral failure had developed in 8 (2 before week 24 and 6 after). Genotypic resistance testing was successful in 6/8 cases and 3/6 samples showed integrase mutation: 155H (n=1), 263K (n=1) and a new mutation not previously described for dolutegravir 230R (n=1).
This met the prespecified criteria for stopping the study and all participants added dual NRTIs to return to triple therapy ART. Virological failure occurred significantly less compared in the 48 week control group (3/152 vs 8/96, p=0.03) and the study concluded: “The genetic barrier of dolutegravir monotherapy is insufficient to allow for maintenance monotherapy”.
Dolutegravir plus lamivudine dual therapy
While monotherapy is clearly not now recommended, even in research, several ongoing studies are looking at whether dual therapy with lamivudine maintain viral load and limit the risk of viral rebound.
Data on this approach was reported from the ANRS LAMIDOL study – an ongoing open-label, single-arm, multicentre trial that switched 110 patients on PI-, NNRTI- or INI-based first-line triple ART to dual therapy of dolutegravir 50 mg and lamivudine 300 mg, both taken together once daily.
Entry criteria included having an undetectable viral load for more than two years, a nadir CD4 count >200 cells/mm3, and no previous drug resistance.
For the first eight weeks (phase 1), the PI (22%), NNRTI (58%) or INI (20%) was switched to dolutegravir, leaving dual NRTIs unchanged. Then from weeks 8 to 56 (phase 2), participants switched the dual NRTIs to lamivudine, remaining on dolutegravir plus lamivudine dual therapy.
Phase 1 enrolled from October 2015 to February 2016 in 19 HIV clinics in France. At week 8, six participants did not roll-over in phase 2; three due to intolerance to dolutegravir and three due to viral load > 50 copies/mL.
Baseline demographics included 86% male, 72% MSM, median age 45 years (range 24 to 70), median time since diagnosis 6.3 years (range 2.3 to 24.5), median time on ART 4.0 years (range 0.5 to 11.3). Median CD4 count was 743 cells/mm3 (range 373 to 1115) and CD4 nadir was 339 cells/mm3 (range 203 to 1155).
All participants have reached week 48, including 40 weeks on dual therapy. One patient had viral rebound after 4 weeks on dual therapy confirmed at 77 copies/mL at week 8, despite adequate plasma C12h of dolutegravir (2401 ng/mL) and lamivudine (299 ng/mL). One patient was lost to follow-up after 32 weeks on dual therapy and one participant had their treatment changed after 40 weeks, based on their doctor’s decision.
The only drug-related serious side effect was hospitalisation due to suicidal ideation during phase 1 in a patient with previous psychiatric disorders. Seven other serious events were judged unrelated to study drugs.
These researchers noted that all participant will reach 48 weeks of dual therapy by March 2017, but that longer follow up and additional studies are need to investigate this approach.
Patients currently stable on dolutegravir monotherapy should be advised to at least add lamivudine to their current ART or to return to triple ART. This is essential as reported cases of viral rebound are both unpredictable and linked to loss of significant future treatment options.
The Barcelona DOLAM study reported at EACS (Martinez et al) has discontinued the monotherapy arm based on a DSBM recommendation after meeting planned stopping rules of >5% virological failure in any arm (in n=2 patients). Although the DOLAM study has stopped the monotherapy arm it will continue patients in the dual (dolutegravir plus lamivudine) and triple ART groups. Choice of treatment for participants in the monotherapy group is based on the doctor’s choice. 
While some studies (including DOLAM) were very carefully designed, others led to later questions about the level of informed consent to this experimental approach.
Although no cases of drug resistance had previously been reported in dolutegravir studies in treatment naive patients, the implications of integrase inhibitor resistance – with the loss of the option to use the current most effective ARV class – show that the move to monotherapy was optimistically premature.
At least two other large dual therapy studies with lamivudine are still ongoing.
The ACTG is currently running a single arm phase 2 study of dolutegravir plus lamivudine dual therapy in 300 treatment naive patients with viral load <500,000 copies/mL. 
ViiV are currently enrolling a phase 3 study randomising participants to either dolutegravir plus lamivudine or dolutegravir plus TDF/FTC in treatment naive participants with viral load <100,000 copies/mL. 
Unless stated otherwise, references are to the Programme and Abstracts of the 24th Conference on Retroviruses and Opportunistic Infections (CROI 2017), 13-16 February 2017, Seattle, Washington.
- Blanco J et al. Pathways of resistance in subjects failing dolutegravir monotherapy. CROI 2017, 13-16 February 2017, Seattle. Oral abstract 42.
- Wijting I et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial
. (NCT02401828). CROI 2017, 13-16 February 2017, Seattle. Late breaker poster abstract 451LB.
http://www.croiconference.org/sessions/dolutegravir-maintenance-monotherapy-hiv-1-randomized-clinical-trial (abstract and poster)
- Joly V et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL trial
. CROI 2017, 13-16 February 2017, Seattle. Poster abstract 458.
http://www.croiconference.org/sessions/promising-results-dolutegravir-lamivudine-maintenance-anrs-167-lamidol-trial (abstract and poster)
- European Union Drug Regulating Authorities Clinical Trials database [Internet]. London: European Medicines Agency (U.K.). 1995. Identifier 2015-000274-35, An open-label, randomized, controlled clinical trial to assess the safety, tolerability and efficacy of two dolutegravir-based simplification strategies in HIV-infected patients with prolonged virological suppression: DOLAM study.
- ClinicalTrials.gov [internet]. Dolutegravir plus lamivudine dual therapy in treatment naïve HIV-1 patients.
- ClinicalTrials.gov [internet]. An efficacy, safety, and tolerability study comparing dolutegravir plus lamivudine with dolutegravir plus tenofovir/emtricitabine in treatment naïve HIV infected subjects (Gemini 1).