Over six years’ worth of real-world data gathered from people with HIV switching to dolutegravir-based two-drug regimens confirm efficacy comparable to three-drug regimens, aligning with previous findings from clinical trials. Dr Conor Bowman and colleagues at the Royal Free Hospital published these findings in the journal AIDS.
By analysing retrospective patient data from a London teaching hospital, the investigators found high rates of viral suppression both in virologically stable people switching to dolutegravir-based dual therapy and previously untreated people starting with it. Only 1% experienced treatment failure during the analysed period from 2015 to 2021. They also found that the different two-drug regimens had similar rates of viral suppression and tolerability.
The regimens they studied were combinations of dolutegravir with lamivudine (also available as Dovato), dolutegravir with rilpivirine (also available as Juluca) and dolutegravir with emtricitabine. Currently, the combination in Dovato is recommended for people starting treatment, and both Dovato and Juluca are among the recommended switch options for virally suppressed people.
Despite mostly reassuring previous data from clinical trials, many people with HIV and their doctors remain hesitant about dual therapy. The scarce real-world experience and data only worsen their hesitation. These findings further encourage the use of two-drug regimens in people living with HIV.
The investigators analysed electronic patient data and prescription records from adults who took dolutegravir-based two-drug regimens between 2015 and 2021. Of 3133 people attending the Royal Free, a fifth were prescribed dual therapy. Out of 620 users of dual therapy, 561 had enough data to be included in the analysis.
Around half of the participants were of White ethnicity, their median age was 54 years, and the majority were gay and bisexual men.
The two-drug regimens were categorised either as single-tablet regimens where both drugs were co-formulated in a single pill or multi-tablet regimens, where each drug was taken as a separate pill. The majority of the participants (84%) were on a multi-tablet regimen. The authors link the unusually high usage of multi-tablet regimens in this cohort to the fact that they have been prescribed before the single-pill combinations were available.
Among the included participants, 83% were on dolutegravir plus lamivudine, 13% received dolutegravir plus rilpivirine and 3% received dolutegravir plus emtricitabine. Interestingly, the latter combination had not been previously studied as a two-drug regimen. However, because emtricitabine is almost identical to lamivudine, similar outcomes could be expected.
Before taking dual therapy, 98% of the participants were already on ART while nine had not received any treatment. Most of the switches were from a three-drug regimen (83%), 16% switched from an alternative two-drug combination and 1% from monotherapy. Fourteen per cent of the three-drug switches contained dolutegravir in their pre-switch regimens.
At the start of the study, 96% of the people with HIV were undetectable and only 4% had a viral load above 50 copies, which included people who were not on treatment.
The median time the participants were on the dual regimens was 11 months for dolutegravir plus lamivudine or emtricitabine and 28 months for dolutegravir plus rilpivirine.
Nearly all participants were virally suppressed at study end
Of the people who switched to or continued on a two-drug regimen, 99% achieved or maintained viral suppression. Although representing a minor fraction of the analysed cohort, all nine previously untreated people initiating treatment on a two-drug combination also had reached viral suppression by the end of the study period.
Thirteen of the 21 people who had detectable virus at the beginning became virally suppressed at the end of the study. Six of the remaining eight experienced blips and two experienced treatment failure.
The most common reason for discontinuation were neuropsychiatric side effects
Seventy of the participants (12.5%) discontinued treatment at some point, 59 of them due to side effects and 11 due to blips or failure.
The most frequent reasons were neuropsychiatric side effects, which accounted for 42% of all discontinuations, followed by weight gain at 17%.
Dolutegravir has been associated with neuropsychiatric side effects, as reported by post-marketing observations from treatment centres. Similarly, rilpivirine has been linked to worsening depression in some. These findings are in line with expectations.
Discontinuation rates were similar between the three two-drug combinations.
Few virological failures and one instance of resistance occurred
In total, 41 viral blips were recorded in 30 participants. Five people were switched to an alternative regimen while the others continued on their regimen and resuppressed the virus. Blips were more common in people taking multiple tablets, perhaps because single tablets are easier to take and less likely to lead to confusion and missed doses.
Six people had virological failure, defined as either viral loads above 200 or persistently detectable virus below 200, and they discontinued the two-drug combinations. They were switched to a three-drug regimen and four people’s viral load was quickly suppressed, while one developed high viral load and another experienced failure due to non-adherence.
One participant with virological failure had virus that had developed resistance to both integrase and reverse transcriptase inhibitors.
Clinical trials are designed in a way that allows them to control for most variables that could potentially lead to unfavourable results. To achieve this, they use elaborate study designs and refined criteria for participant selection, as well as offering extra support to participants. In real-world settings there are many variables such as previous ART exposure and less-than-ideal adherence that can lead to significantly different outcomes from those observed in trials. The relatively low rates of discontinuations due to side effects, excellent viral suppression and few failures observed in this single-centre cohort study may help to boost doctors’ and patients’ confidence in dual therapy.
Bowman C et al. Real world use of dolutegravir two drug regimens. AIDS 37(5): 785-788, 2023.