First, Dominique Braun from Switzerland presented a small study that assessed whether people who were fully suppressed on triple therapy could be switched to dolutegravir monotherapy. Interestingly, one of his first slides stated that “dolutegravir monotherapy is dead”, as two randomised controlled trials (Blanco 2018, Wijting 2017) have now demonstrated a substantial number of virologic failures with emergence of INSTI resistance during dolutegravir monotherapy. However, the justification for conducting Dr Braun’s trial was that the concept of dolutegravir monotherapy had not been tested in patients who started triple therapy during primary HIV infection (i.e. within six months of estimated HIV infection), and who fully suppressed on their initial triple therapy regimen. He argued that these patients may have a smaller HIV reservoir, less immune activation, and smaller viral diversity, and that these differences may make these patients optimal candidates for treatment simplification with dolutegravir monotherapy.
They enrolled 101 patients aged 18 years or older with documented primary HIV infection (as defined in Braun et al, 2015, CID). Their other eligibility criteria included:
- Initiation of cART within 180 days after estimated date of infection
- No previous treatment interruption
- No previous virologic failure
- Suppressed viral load (<50 copies/ml) for at least 48 weeks.
Their exclusion criteria included:
- One or more major INSTI mutations
- Active hepatitis B infection
- Women who were pregnant, planning to be pregnant, or at risk of pregnancy.
By 2:1 randomisation, 68 participants were switched to dolutegravir monotherapy, and 33 participants continued triple therapy. Subsequently, one of the participants randomised to monotherapy was excluded due to a major protocol violation, because in retrospect he was actually a late-presenter at time of diagnosis, and was not diagnosed during primary HIV infection. This participant also failed dolutegravir monotherapy at week 36.
At 48 weeks, after excluding the participant with a major protocol violation, no other participants failed dolutegravir monotherapy. Hence using a 10% non-inferiority margin, dolutegravir was non-inferior at 48 weeks by both the intention-to-treat analysis and the per-protocol analysis.
The second presentation, by Laurent Hocqueloux from France, presented data from the MONCAY trial, which assessed dolutegravir monotherapy (n=78) vs dolutegravir/abacavir/lamivudine (n=80). To enrol, all participants had to be stable on DTG/ABC/3TC, with an undetectable VL for at least 12 months, and have a CD4 nadir of >100/mm3. The primary outcome was the proportion or participants with an undetectable HIV viral load at week 24. At week 24, 2 participants in the DTG arm had a virologic non-response, with 84 and 55 copies/ml respectively. Both of these participants had no integrase mutations, and fully suppressed after treatment intensification with triple therapy. However, during extended follow-up beyond 24 weeks, they observed a further 5 failures in the DTG arm, and 2/5 (40%) had INSTI mutations, and these had not been observed at baseline
Both of these presentations elicited heated debate from the audience.
- Viral rebound can be unpredictable during dolutegravir monotherapy, and has only been observed during longer term follow-up (beyond 24 weeks).
- There are serious ethical questions around conducting monotherapy studies, as these risk the induction of INSTI resistance mutations, thereby compromising the future health of participants.
- Small studies may not have adequate power to detect failure of dolutegravir monotherapy, and hence have limited value, and make them ethically questionable.
- When conducting non-inferiority studies of monotherapy in patients who have been well-suppressed on a first line regimen, a non-inferiority margin of 10% may too large to be clinically meaningful.
- Laura Waters (Mortimer Market) raised the important point that simplification studies carry considerable risk for study participants, and that participants should be re-consented if important data becomes available during the study. In the case of these studies, when the DOMONO dolutegravir monotherapy study (Wijting, Lancet HIV 2017) showed low but unacceptable virologic failure after week 24, this information should have been communicated to every participant in these studies through a re-consent process.
It should be highlighted that ViiV Healthcare (who make dolutegravir) did not support these trials, and they do not support the idea of conducting dolutegravir monotherapy studies.
As a personal point of reflection, when we conduct clinical trials, the participants (our patients) often have faith that we will not place them in harm’s way. Even if the consent process highlights that the trial may carry some risk, they are often reassured by the fact that the trial is conducted by trusted clinicians. We, as clinician researchers, have a duty to not place our patients in harm’s way for the sake of a clinical trial.