HTB

Meta-analysis of dolutegravir in naive, experienced and switch studies

Polly Clayden, HIV i-Base

A meta-analysis of 7340 participants in 13 randomised trials found efficacy and safety benefits for starting dolutegravir compared with other antiretrovirals in both naive and experienced participants. [1] In the four switch studies in participants with undetectable viral load on their current ART, however, changing to dolutegravir was associated with more adverse events and discontinuations.

Investigators from Liverpool University, Imperial College London, London, and Chelsea and Westminster Hospital in the UK are conducting ongoing reviews of antiretrovirals under consideration for recommendation by WHO and national departments of health in low- and middle-income countries. [2–5] An update of the dolutegravir meta-analysis was presented at the Fourth Joint Conference of BHIVA/BASHH.

For this update, a PUBMED/Embase search identified 13 trials. Of these, seven were in ART naive participants (ARIA, FLAMINGO, Gilead-1489, Gilead-1490, SINGLE, SPRING-1, SPRING-2), two were in ART experienced (DAWNING, SAILING) and there were four switch trials in people with viral load suppression (NEAT 022, STRIIVING, SWORD-1, SWORD-2).

In the nine trials of naive and experienced patients (n=5348), dolutegravir showed 7% higher rates of viral load suppression <50 copies/mL (p=0.002). This effect was consistent for all three comparitor drug classes: NNRTIs (p=0.002), PIs (p=0.0003) and integrase inhibitors (p=0.05).

There was also a 2% lower risk of discontinuation for adverse events (p=0.03) in these nine studies for people starting in dolutegravir arms. There was consistent effect for comparison of with NNRTIs, PIs and other integrase inhibitors, but no decline in protocol-defined virological failure or risk of drug resistance.

But, in the four switching studies (n=1992), there were significantly more Grade 1–4 adverse events and adverse events associated discontinuation (both p<0.001) in people taking dolutegravir. The investigators noted that this increased risk of adverse events after switch has not been observed in switching studies of other antiretrovirals, including elvitegravir, bictegravir and darunavir/r.

They concluded that “If patients are already tolerating current antiretroviral treatment, the risks of switching to dolutegravir could outweigh the benefits.”

comment

These findings need to be considered in the context that people who are stable on antiretroviral regimens before entry to a switch study are likely to be doing well and tolerating their regimen.

The observation that this increased risk of adverse events has not been seen in switching studies of other antiretrovirals is notable, but might not allow for the change in dosing recommendations that have developed post-approval.

For example, sleep disturbance and insomnia that were early reasons for switching but that anecdotally resolved by taking dolutegravir as a morning dose.

References

  1. Hill A et al. Meta-analysis of dolutegravir for 7340 patients in 13 trials: effects of current HIV RNA suppression on efficacy and safety. 4th Joint BHIVA/BASHH Conference, 17 – 20 April 2018, Edinburgh. Poster abstract P16. HIV Medicine, 19 (Suppl. 2), s21–s152.
  2. Hill A and Mitchell N. Meta-analysis of safety for DTG versus other ARVs in randomised trials: analysis of cardiovascular, CNS and IRIS endpoints. 16th EACS, 2017, Milan. Poster abstract PE12/17.
  3. Clayden P. Studies on dolutegravir and sleep, cardiovascular and CNS side effects, and risk of IRIS. HTB. 28 November 2017.
    http://i-base.info/htb/32830
  4. Hill AM et al. Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomised trials.Curr Opin HIV AIDS. 13 (2) March 2018.
    https://journals.lww.com/co-hivandaids/Abstract/2018/03000/Risks_of_cardiovascular_or_central_nervous_system.3.aspx
  5. Meta-analysis reports no significant risk of cardiac, IRIS or suicide with dolutegravir. HTB. 21 February 2018.
    http://i-base.inf,11o/htb/33521

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