More than six years of real-world data collected from people living with HIV switching to dolutegravir-based two-drug regimens confirm comparable efficacy to three-drug regimens, consistent with previous clinical trial results. Dr Conor Bowman and colleagues at the Royal Free Hospital have published these findings in the journal AIDS.
Analyzing retrospective patient data from a London teaching hospital, the researchers found high rates of viral suppression both in virologically stable people who switch to dolutegravir-based dual therapy and in previously untreated people who start on it. Only 1 percent experienced treatment failure during the analyzed period of 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 Due), dolutegravir with rilpivirine (also available as Juluca) and dolutegravir with emtricitabine. Currently, the combination in Due it is recommended for people starting treatment, and both Due AND Juluca are among the recommended switching options for people with viral suppression.
Despite mostly reassuring previous data from clinical trials, many people with HIV and their doctors remain hesitant about dual therapy. Poor experience and real-world data only make their hesitation worse. These findings further encourage the use of two-drug regimens in people living with HIV.
I study
Researchers analyzed electronic patient data and prescription records from adults who took dolutegravir-based two-drug regimens between 2015 and 2021. Of the 3,133 people who attended Royal Free, one-fifth were prescribed dual therapy. Of 620 dual therapy users, 561 had sufficient data to be included in the analysis.
About half of the participants were white, their median age was 54, and the majority were gay and bisexual men.
Two-drug regimens have been classified as single-tablet regimens in which both drugs were co-formulated into a single pill, or multiple-tablet regimens, in which each drug was taken as a separate pill. The majority of participants (84%) were on a multi-tablet regimen. The authors link the unusually high use of multi-tablet regimens in this cohort to the fact that they were prescribed before single-pill combinations were available.
Of the included participants, 83% were receiving dolutegravir plus lamivudine, 13% received dolutegravir plus rilpivirine, and 3% received dolutegravir plus emtricitabine. Interestingly, the latter combination had not previously been studied as a two-drug regimen. However, since emtricitabine is nearly identical to lamivudine, similar outcomes might be expected.
Before taking the dual therapy, 98% of the participants were already on ART while nine had not received any treatment. The majority of switches were from a three-drug regimen (83%), 16% switched from an alternative two-drug combination, and 1% from monotherapy. Fourteen percent of the three-drug swaps contained dolutegravir in their pre-switch regimens.
At the start of the study, 96% of people with HIV were undetectable and only 4% had a viral load greater than 50 copies, which included people who weren\’t on treatment.
The median time participants spent on the dual regimen was 11 months for dolutegravir plus lamivudine or emtricitabine and 28 months for dolutegravir plus rilpivirine.
Nearly all participants were virally suppressed at the end of the study
Of people who switched or continued on a two-drug regimen, 99% achieved or maintained viral suppression. Although they represent a smaller fraction of the analyzed cohort, all nine previously untreated people who started treatment with a two-drug combination had also achieved viral suppression by the end of the study period.
Thirteen of the 21 people who had detectable virus to begin with became virally suppressed by the end of the study. Six of the remaining eight experienced nuisance signals and two experienced treatment failure.
The most common reason for discontinuation was neuropsychiatric side effects
Seventy of the participants (12.5%) stopped treatment at some point, 59 of them due to side effects and 11 due to problems 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 from treatment center postmarketing observations. Similarly, rilpivirine has been linked to worsening depression in some. These results are in line with expectations.
Discontinuation rates were similar among the three two-drug combinations.
There have been few virological failures and one case of resistance
In total, 41 viral blips were recorded in 30 participants. Five people switched to an alternative regimen while the others continued their regimen and suppressed the virus. The blips were more common in people who took multiple tablets, perhaps because individual tablets are easier to take and less likely to lead to confusion and missed doses.
Six people had virologic failure, defined as viral load greater than 200 or persistently detectable virus less than 200, and discontinued the two-drug combinations. They switched to a three-drug regimen, and four people\’s viral loads were rapidly suppressed, while one developed a high viral load and another suffered failure due to non-adherence.
One participant with virologic failure had virus that developed resistance to both integrase and reverse transcriptase inhibitors.
Conclusion
Clinical trials are designed in a way that allows them to control for most variables that could potentially lead to unfavorable outcomes. To achieve this, they use elaborate study designs and refined criteria for selecting participants, as well as offering extra support to the participants. In real-world settings there are many variables such as previous exposure to ART and less-than-ideal adherence that can lead to significantly different outcomes than those seen in studies. The relatively low discontinuation rates due to side effects, excellent viral suppression, and few failures observed in this single-center cohort study may help bolster physician and patient confidence in dual therapy.
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