Dolutegravir-based single-drug therapy was an effective long-term maintenance regimen in people who had started treatment soon after acquiring HIV in a small study published in the journal Clinical Infectious Diseases. Participants on dolutegravir alone experienced no treatment failure while their immunological and virological features remained stable throughout the four-year follow-up. These findings from the extended Early Simplified trial suggest the possibility of dolutegravir-based single-drug therapy for a select group of people with HIV, but there are caveats.
Due to excellent virological efficacy, dolutegravir has been tried as a single-drug therapy (monotherapy) several times before. Yet, those attempts have invariably led to unsatisfactory long-term viral suppression. Unlike previous studies, this one looked at the possibility of maintaining viral suppression on monotherapy specifically in people who had started treatment very early (in the first six months after infection) and had been continuously undetectable.
Those who start treatment during this stage, known as primary infection, have a less diverse virus pool, better immune recovery, and possibly smaller viral reservoir, which according to the authors may have helped the monotherapy be effective in this group.
The concept is appealing, as fewer drugs would mean reduced costs, fewer side effects and potentially less long-term harmful effects. Although the idea may seem novel, monotherapy is not new to HIV treatment. In fact, it has also been tried before with protease inhibitors, consistently leading to poor viral suppression.
The study points to the possibility of using dolutegravir monotherapy only in a subset of people with HIV. It reinforces the idea that dolutegravir is a very potent drug and that people treated early may have distinct responses. However, unconvincing results from previous studies and lack of evidence of efficacy apart from this study effectively mean that dolutegravir monotherapy does not justify the risks for most people with HIV. The most serious risk is the development of resistance to integrase inhibitors – as seen in previous studies – making the entire drug class unavailable for the person. Given that integrase inhibitors are central to HIV treatment, this would significantly limit treatment options.
Implementing this approach would be challenging: identifying people in early infection is not easy and reliable as there are no categorical markers that can undoubtably prove when a person acquired the virus. Moreover, former chair of BHIVA, Dr Laura Waters commented on Twitter: ‘’The fact that fewer than 25% of those screened were eligible highlights that this strategy would only be for a limited population’’. The close monitoring of participants in the study also fails to reflect the more dynamic real-world settings.
Criticism from other HIV experts also addressed the small sample size of the study group. This makes the possibility of error and chance results very real; a larger study may not be able to replicate the same results.
In the randomised trial, Dr Emily West and her colleagues at the University of Zurich tried to determine whether dolutegravir alone could be as effective as standard therapy (composed of three drugs) in maintaining viral control. They worked with a Swiss cohort of people with HIV who had started triple-drug therapy during primary infection (defined as the first six months following acquisition of HIV). The participants had to have been continuously undetectable during the preceding 48 weeks. Other requirements were lack of past treatment failure, treatment interruption or major resistance to integrase inhibitors.
From 2015 to 2017, 101 participants were enrolled in the study, a third of whom continued their standard therapy, while the other 68 switched to dolutegravir monotherapy. Subsequently, four participants from the monotherapy group and three from the standard therapy group were excluded from the analysis. The reasons for exclusion varied and while most were not related to treatment, one participant was excluded as it was established that they had not met the study’s eligibility criteria.
The characteristics of participants were very similar across both treatment groups. The majority were of White ethnicity, their median age was 42 years, and there were only four women. Reflective of long-term stable viral suppression, their median CD4 count stood at 716. The median time from HIV acquisition to starting treatment was 38 days and before entering the study they had been on treatment on average for about three and a half years.
Following the interim analysis at 48 weeks showing 100% viral suppression on monotherapy, the study team decided to extend the follow-up for another three years. At week 96 they also lifted the randomisation so that people could switch between standard therapy and monotherapy if they wished to. At that point the study became observational and there were additional analyses of outcomes at weeks 96, 144 and 192 (the end of the study, almost four years).
Similar rates of viral blips and CD4 counts on both therapies
Throughout the study CD4 counts remained high with a tendency to gradually increase, and there were no significant differences between the groups. Three people in each group experienced viral blips (a single viral load measurement above 50 copies).
Similar rates of reservoir shrinkage in both groups
While at 48 weeks the HIV reservoir (the virus that stays in hiding in different body sites and can start multiplying once treatment is stopped) seemed to shrink faster on monotherapy compared to standard therapy, at four years there was no significant difference.
Fewer changes of treatment due to side effects on monotherapy
Twenty-two per cent of the participants on monotherapy and 27% on standard therapy experienced side effects that were related to treatment. However, only one participant discontinued monotherapy due to side effects in contrast to five people (15%) on standard therapy. There was a general trend of weight gain that did not differ between groups.
Adequate dolutegravir concentrations
Dolutegravir levels were measured both in the monotherapy group and in those taking dolutegravir in the standard therapy group. The drug’s concentrations in blood and cerebrospinal fluid (the fluid that surrounds the brain and the spinal cord) remained within the therapeutic range (sufficient to neutralise the virus).
Four years later, there were no treatment failures in either group
None of the participants who completed the entire follow-up experienced virological failure.
These results were most likely also helped by the nearly 100% adherence the participants reported throughout the study.
Another analysis (intention-to-treat analysis) that included those participants who at some point failed to comply with study requirements also showed nearly identical results, however viral suppression on monotherapy dropped to 99%. This is because there was one participant who experienced virological failure and was excluded when it was realised that they had not met the enrolment criteria at study entry. It was found that the participant had started treatment after the phase of primary infection.
During primary infection, and particularly the acute phase (usually defined as the first three months past HIV acquisition) there are distinct events that take place. The immune system is still robust and tries to mount a strong response against the virus, while the virus tries to adapt to those responses by creating many ‘versions’ of itself through mutation. The virus also tries to establish hiding places in the body that we call reservoirs where the immune system cannot detect and neutralise it, but the reservoir may be relatively small at this stage. It is these features of primary infection that may make the virus more susceptible to being outmuscled. Bearing this in mind, the study team selected an ideal set of participants who would have the best response to monotherapy.
While the results reported in this elaborate study are very encouraging, they only prove that different groups of people with HIV may benefit from different, more tailored approaches. They also widen our understanding of what is possible in terms of HIV treatment and what is plausible. However, many previous studies indicate that monotherapy, including dolutegravir-based monotherapy, does not seem to be a viable option for people with HIV in general.
There are already two dual therapy options based on dolutegravir (Juluca and Dovato) that use fewer drugs than standard therapy and achieve optimal results with a comparable safety profile to and lower risks than monotherapy. Besides, the exceptionally high adherence to treatment seen in this study would be very difficult to achieve in real-world settings.
West E et al. Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): a randomized, controlled, multi-site, non-inferiority trial. Clinical Infectious Diseases, ciad366, online ahead of print, 20 June 2023 (open access).
Braun DL et al. Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial. Clinical Infectious Diseases 69: 1489–1497, 2019 (open access).